INSTRUCTOR MANUAL for Advanced Nutrition and Human Metabolism, 7e Sareen Gropper, Jack Smith, Timoth by StudyGuide

INSTRUCTOR MANUAL for Advanced Nutrition and Human Metabolism, 7e Sareen Gropper, Jack Smith, Timothy Carr.

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 1 – The Cell: A Microcosm of Life Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Group Project Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Responding to Research – Mitochondria and Aging Worksheet 2: Labeling It – A Eukaryotic Cell

Chapter Outline I. Introduction 1. This chapter provides a brief review of the basics of a cell, including cellular components, biological energy, and an overview of a cell’s natural life span. 2. Key Terms a. Cells – basic living, structural, and functional units of the human body b. Eukaryotic cells – multicellular organisms c. Prokaryotic cells – primitive cells d. Plasma membrane – sheet-like structure that encapsulates and surrounds the cell, allowing it to exist as a distinct unit 3. Figures and Tables a. Figure 1.1 – three-dimensional depiction of a typical mammalian liver cell II. Components of Cells A. Plasma Membrane 1. Sheet-like structure that encapsulates and surrounds the cell. It is asymmetrical and considered to be a fluid structure 2. Key Terms a. Hydrophobic – molecule or part of molecule that repels water but has strong affinity for nonpolar substances b. Receptors – macromolecules that bind a signal molecule with a high degree of specificity that triggers intracellular events c. Enzymes – protein catalysts that increase the rate of a chemical reaction in the body 3. Figures and tables a. Figure 1.2 – lipid bilayer structure of biological membranes b. Figure 1.3 – fluid model of cell membrane. Lipids and proteins are mobile and can move laterally in the membrane

B. Cytoplasmic Matrix 1. Consists of filaments or fibers and provides the cell with structural support, framework, network to direct movement, means of independent location, pathway for intercellular communication, and possible transfer of RNA and DNA 2. Key Terms a. Microtubules – hollow, cylindrical cytoskeletal structures composed of the protein tubulin that act to support the cell structure b. Intermediate filaments – strong, ropelike cytoskeletal fibers that are made of protein and that function to provide mechanical stability to cells c. Microfilaments – solid cytoskeletal structures made of a double-helix polymer of the protein actin that play a role in cell motility 3. Microtubules, intermediate filaments, and microfilaments – make up the cytoskeleton 4. Structural arrangement a. Hexose monophosphate shunt – pentose phosphate pathway 5. Figures and tables a. Figure 1.4 – the cytoskeleton provides a structure for cell organelles, microvilli, and large molecules C. Mitochondrion 1. Cellular organelle that is the site of energy production by oxidative phosphorylation and the site of tricarboxylic acid cycle 2. Key terms a. Mitochondria – primary sites of oxygen use and ATP production in cells b. Oxidative phosphorylation – pathway in the mitochondria that makes ATP from ADP and Pi c. Electron transport chain – sequential transfer of electrons from reduced coenzymes to oxygen that is coupled with ATP formation and occurs within the mitochondria 3. Mitochondrial membrane – consists of a matrix or interior space surrounded by a double membrane 4. Mitochondrial matrix – metabolic enzyme systems that function by catalyzing reactions of the tricarboxylic acid and fatty acid oxidation 5. Figures and tables a. Figure 1.5 – the mitochondrion b. Figure 1.6 – overview of a cross section of a mitochondrion D. Nucleus 1. Largest organelle within the cell, regulating most cellular activities 2. Key terms a. Nuclear envelope – composed of an inner and an outer membrane; surrounds the cell nucleus b. Nucleolus – region of the nucleus containing condensed chromatin and sites for synthesizing ribosomal RNA c. Genes – section of chromosomal DNA that codes for a single protein d. Genome – sum of all the chromosomal genes of a cell e. Nucleotides – phosphate esters of the 5ʹ-phosphate of a purine or pyrimidine in N-glyosidic linkage with ribose or deoxyribose; occurs in nucleic acids

f. Complementary base pairing – pairing of nucleotide bases in two strands of nucleic acids; A pairs with T or U, while G pairs with C g. Replication – synthesis of a daughter duplex DNA molecule identical to the parental duplex DNA h. Transcription factors – auxiliary proteins that bind to specific sites in the DNA and alter the transcription of nearby genes i. Sense strand – the strand of DNA that serves as a template for mRNA j. Introns – noncoding regions of a gene k. Exons – coding regions of a gene l. Anticodons – three-base sequences of nucleotides within transfer RNA molecules m. Elongation – (1) extension of the polypeptide chain of the protein product during protein synthesis, (2) the addition of carbons to a fatty acid chain n. MicroRNAs – small noncoding RNAs that silence gene expression by binding to mRNA to inhibit its translation and/or promote its degradation 3. Nucleic acids – macromolecules of nucleotides; consist of a nitrogenous core, a pentose sugar, and a phosphate 4. Cell replication – synthesis of daughter DNA identical to the parental DNA 5. Transcription – taking genetic information in a single strand of DNA and making a specific sequence of bases in a messenger RNA chain 6. Translation – process by which genetic information in an mRNA molecule is turned into the sequence of amino acids in the protein 7. Control of gene expression – controlled through transcription, processinglevel control mechanisms determine the path by which mRNA is translated into polypeptide and translation-level control mechanisms determine which mRNA is translated 8. Figures and tables a. Figure 1.7 – steps of protein synthesis b. Figure 1.8 – DNA replication E. Endoplasmic Reticulum and Golgi Apparatus 1. The organelles function together to create a mechanism for communication from the innermost part of the cell to its exterior 2. Key terms a. Endoplasmic reticulum – network of membranous channels pervading the cytosol and providing continuity between the nuclear envelope, the Golgi apparatus, and the plasma membrane b. Sarcoplasmic reticulum – smooth endoplasmic reticulum that is found in muscle cells and is the site of the calcium pump c. Cytochromes – heme-containing proteins that serve as electron carriers d. Oxidation – enzymatic reaction in which oxygen is added to, or hydrogen and its electrons are removed from, the reactant e. Lipophilic – state of being attracted to lipids and thus repelled by water f. Hydrophilic – refers to a molecule or part of a molecule having a strong affinity for water and other polar substances g. Golgi apparatus – the part of the cell responsible for modifying macromolecules synthesized in the endoplasmic reticulum and packaging them to be transported to the cell surface or cytosol

F. Lysosomes and Peroxisomes 1. Aid in cell’s digestion and oxidative catabolic reactions 2. Key terms a. Lysosomes – cell organelles that contain digestive enzymes b. Peroxisomes – cell organelles containing enzymes that perform oxidative catabolic reactions c. Catabolism – process by which organic molecules are broken down III. Selected Cellular Proteins A. Receptors 1. Highly specific proteins located in the plasma membrane and act as recognition markers 2. Key terms a. Ligands – small molecules or minerals that bind to a larger molecule 3. Receptors that generate internal chemical signals – an internal chemical signal is generated following interaction between some receptors and ligands 4. Receptors that function as ion channels – in some cases, the binding of the ligand to its receptor causes a voltage change, which then becomes the signal for a cellular response 5. Receptors that internalize stimuli – a stimulus is internalized through a stimulus 6. Receptor’s role in homeostasis – receptors that respond to changes in the external conditions 7. Figures and tables a. Figure 1.9 – example of an internal chemical signal by a second messenger b. Figure 1.10 – internalization of a stimulus into a cell via its receptor B. Catalytic Proteins (Enzymes) 1. These are enzymes that are catalysts and take part in reactions but are not part of the final product of that reaction 2. Key terms a. Oxidoreductases – enzymes that catalyze all reactions in which one compound is oxidized and another is reduced b. Transferases – enzymes that catalyze reactions not involving oxidation and reduction in which a functional group is transferred from one substrate to another c. Hydrolases – enzymes that catalyze cleavage of bonds between carbon atoms and some other kind of atom by the addition of water d. Lyases – enzymes that catalyze cleavage of carbon–carbon, carbon– sulfur, and certain carbon–nitrogen bonds without hydrolysis or oxidation–reduction e. Isomerases – enzymes that catalyze the interconversion of optical or geometric isomers f. Ligases – enzymes that catalyze the formation of bonds between carbon and other atoms g. Ischemia – deficiency of blood in a tissue h. Oncogenes – genes capable of causing a normal cell to convert to a cancerous cell © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. Reversibility – the same enzyme catalyzes a reaction in both directions 4. Regulation – anabolic and catabolic reactions are kept balanced a. Covalent modification – enzyme is inactive until a posttranslational modification is made b. Allosteric enzyme modulation – a secondary regulatory mechanism that is used by certain enzymes called allosteric enzymes. These enzymes possess another site besides the catalytic site c. Induction – creates changes in the concentration of certain inducible enzymes by increasing enzyme synthesis 5. Examples of enzyme types – enzyme participation depends on where the enzyme is located through the cell 6. Clinical applications of cellular enzymes – enzymes are synthesized intracellularly, and most function within the cell they are formed in. Enzymes must have high degree of organ or tissue specificity, steep concentration gradient of enzyme activity between the interior and exterior of cells, must function in the cytosol of the cell, and must be stable for a reasonable time period in the vascular compartment IV. Apoptosis 1. Programmed cell death 2. Key terms a. Apoptosis – programmed cell death b. Caspases – family of cysteine proteases involved in the degradative events during apoptosis c. Tumor necrosis factor – a cytokine released by immune cells and mast cells that causes destruction of tumors and migration of neutrophils toward the site of bacterial infections d. Cytokines – generic term for nonantibody protein messengers released from a macrophage or lymphocyte that is part of an intracellular immune response e. Oncosis – a prelethal pathway accompanied by cellular swelling, organelle swelling, and increased membrane permeability that lead to cell death f. Motility – movement V. Biological Energy A. Energy Release and Consumption in Chemical Reactions 1. Energy derived from macromolecules 2. Key terms a. Macronutrients – dietary nutrients that supply energy, including fats, carbohydrates, and proteins 3. Figures and tables a. Figure 1.11 – adenosine triphosphate b. Figure 1.12 – a comparison of the simple combustion and the metabolic oxidation of the fatty acid palmitate B. Expressions of Energy 1. Key terms a. Free energy – the potential energy inherent in the chemical bonds of nutrients © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

b. Exothermic – a reaction in which the reactants have more free energy than the products; it therefore gives off energy as heat c. Endothermic – a reaction in which the products have more free energy than the reactants; it therefore requires energy d. Transition state – energy level at which reactant molecules have been activated and can undergo an exothermic reaction e. Activation energy – energy introduced into the reactant molecules to activate them to the transition state so that an exothermic reaction can take place 2. Units of energy – calories are the unit of energy used throughout this text. Kcal is used to represent 1,000 calories. 3. Free energy – potential energy inherent in the chemical bonds of nutrients is released if the molecules undergo oxidation 4. Exothermic and endothermic reactions – reactions either involving energy or releasing energy 5. Activation energy – energy required for a reaction to occur. Exothermic reactions are favored since they do not require external energy input 6. Cellular energy – how the cell derives its energy from a series of chemical reactions 7. Reversibility of chemical reactions – most cellular reactions are reversible, meaning an enzyme can catalyze in both directions 8. Standard free energy change – a temperature of 298 K, a pressure of 1.0 atm, and the presence of both the reactants and the products at their standard concentrations, namely 1.0 mol/L 9. Equilibrium constant and standard free energy change – the equilibrium constant of a reaction determines the sign and magnitude of the standard free energy change 10. Standard pH – 7.0 is the adopted standard pH value 11. Nonstandard physiological conditions – physiological standard conditions do not often exist, which may explain why reactions proceed when the conditions are not standard 12. Figures and tables a. Figure 1.13 – the uphill–downhill concept illustrating energy-releasing and energy-demanding processes b. Figure 1.14 – example of a shift in the equilibrium by changing from standard conditions to physiological conditions C. The Role of High-Energy Phosphate in Energy Storage 1. ATP can be used as a universal source of energy through the hydrolysis of the phosphate bonds 2. Figures and tables a. Figure 1.15 – examples of very high-energy phosphate compounds b. Figure 1.16 – an illustration of how ATP is generated from the coupling of ADP and phosphate through the oxidative catabolism of nutrients and in turn, is used for energy-requiring processes D. Coupled Reactions in the Transfer of Energy 1. Reactions that require energy and reactions that yield energy 2. Figures and tables a. Figure 1.17 – examples of high-energy phosphate bonds being transferred © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

b. Figure 1.18 – exothermic reactions E. Reduction Potentials 1. Ability of a compound to be reduced by accepting an electron/s 2. Key terms a. Standard reduction potential – tendency of a molecule to donate or receive electrons b. Hydrogen atoms – chemical element of hydrogen containing one proton and one electron VI. Summary A. Plasma Membrane 1. Ability to protect the cell while adjusting to the environment B. Communication of the Cell 1. Cell’s ability to use the cytosol, microtrabecular network, and the endoplasmic reticulum and Golgi apparatus to communicate between the nucleus and plasma membrane C. Division of Labor among Cell Components D. Nucleus 1. Ability to ensure all needed proteins are synthesized E. Apoptosis 1. Programmed cell death

Resources In-Text Web Sites All About the Human Genome Project (HGP) In-Text Suggested Readings • Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116:281–97. • Remely M, Stefanska B, Lovrecic L, Magnet U, Haslberger AG. Nutriepigenomics: the role of nutrition in epigenetic control of human diseases. Curr Opin Clin Nutr Metab Care. 2015; 18:328–33. Additional Resource • Sebastián D, Acín-Pérez R, Morino K. Mitochondrial health in aging and age-related metabolic disease. Oxid Med Cell Longev. 2016, 5831538. Article ID Mitochondrial Health in Aging and Age-Related Metabolic Disease

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. • The endoplasmic reticulum has multiple roles including translation and protein regulation. What are some disorders that the endoplasmic reticulum plays a role in? • Answer: cystic fibrosis, type I diabetes, neonatal diabetes.

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What serves as the electron acceptor and donor throughout the oxidation and reduction of glucose? •

Answer: NADH; when NAD+, it is able to accept the hydrogen; when NADH, it is able to donate the hydrogen.

Assignment – Group Project •

You have learned about the organelles of the eukaryotic cell and how each has a vital function. Find a partner and draw a diagram or a process map showing how a cell takes the DNA and produces a protein. Describe which organelles are involved in the process and which processes are occurring throughout the cell. • Rubric: The diagram should highlight the DNA in the nucleus undergoing transcription to become RNA to messenger RNA. From there, it should show the mRNA leaving the nucleus and entering the cytoplasm to be translated by the ribosomes into proteins.

Answer Keys Worksheet 1: Responding to Research – Mitochondria and Aging 1. b 2. d 3. reduces; reduction 4. Reduce risks of heart disease and diabetes by eating a healthy diet and being active. Worksheet 2: Labeling It – A Eukaryotic Cell A. Mitochondria – energy, ATP synthesis, cellular respiration B. Golgi apparatus – packages proteins, lipid synthesis for protein packaging C. Rough endoplasmic reticulum – contains ribosomes responsible for protein synthesis D. Nucleolus – ribosomal RNA synthesis

Worksheet 1: Responding to Research – Mitochondria and Aging Mitochondria are organelles present in both eukaryotic and prokaryotic cells. Their main function is energy production through many oxidation/reduction steps. They are also key elements in the aging process. Read the following article and then respond to the questions. • Sebastián D, Acín-Pérez R, Morino K. Mitochondrial health in aging and age-related metabolic disease. Oxid Med Cell Longev. 2016, 5831538. Article ID Mitochondrial Health in Aging and Age-Related Metabolic Disease 1. When biogenesis is increased, mitochondrial function becomes more efficient. a. True b. False __________ 2. Maria has recently been informed that she has coronary heart disease and that this puts her at more risk for mitochondrial dysfunction. She wants to understand more about her condition. What is the best explanation to give to her? a. It is a natural aging process that is not affected by coronary heart disease. b. It is a natural aging process and because she does not have diabetes, she will be fine. c. It involves oxidation damage that only affects peripheral neurons. d. It is caused by oxidation damage that might be reduced through the use of antioxidants. __________ 3. Mitochondrial mass _______ as the body ages, leading to a(n) ______ in oxidation. a. reduces; reduction b. reduces; increase c. increases; reduction __________ 4. According to this article, what are two measures that can be taken for mitochondrial health?

Worksheet 2: Labeling It – A Eukaryotic Cell Label the letters in the diagram below and describe the function of each of the organelles.

A. ____________________________________________________________________

B. ____________________________________________________________________

C. ____________________________________________________________________

D. ____________________________________________________________________

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 2 – The Digestive System: Mechanism for Nourishing the Body Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Project Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Responding to Research – Malabsorption Disorders Worksheet 2: Labeling It – Transport

Chapter Outline I. Introduction 1. This chapter covers the organs and processes involved in digestion and absorption of the nutrients consumed and needed. The body needs six classes of nutrients: carbohydrates, lipids, proteins, vitamins, minerals, and water II. The Structures of the Digestive Tract and the Digestive and Absorptive Processes 1. The digestive tract consist of organs digestive, absorbing, and assisting in the digestion and absorption process 2. Key Terms a. Endocrine – all the body’s hormone-secreting glands b. Zymogens – an inactive form of an enzyme 3. Figures and Tables a. Figure 2.1 – the digestive tract and its accessory organs b. Figure 2.2 – the sublayers of the small intestine c. Table 2.1 – digestive enzymes and their actions A. Oral Cavity 1. Consists of the mouth and pharynx; entryway to the digestive tract 2. Key Terms a. Lingual lipase – pertains to the tongue and digestion of lipids 3. Figures and Tables a. Figure 2.3 – secretions of the oral cavity B. Esophagus 1. Receives the bolus from the oral cavity and passes it to the stomach 2. Key Terms a. Reflex – an involuntary response to a stimulus b. Nervous system – the system of nervous tissue made up of neurons and glial cells © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. Selected disorders of the esophagus – gastroesophageal reflex disease C. Stomach 1. Receives the bolus of food from the esophagus and further digests. Consists of four main regions: cardia, fundus, body, and antrum/pyloric portion 2. Key Terms a. Chyme – partially digested food b. Mucin – glycoproteins found in some body secretions, such as saliva c. Prostaglandins – biologically active compounds derived from linoleic or αlinolenic acids d. Antral – pertaining to the antrum; the lower or distal portion of the stomach e. Osmolarity – a measure of the solute particle numbers expressed as osmoles of solute particles in 1 L of solution (osm/L); in dilute aqueous solutions as found in the human body, only a small numerical difference exists between osmolarity and osmolality f. Bile – a body fluid made in the liver and stored in the gallbladder that participates in emulsifying fat and forming micelles for fat absorption g. Insulin – hormone secreted by the pancreas in response to rising blood glucose derived from food; promotes glycose uptake into muscles and adipose tissue, thus normalizing blood glucose concentration 3. Gastric juice – contains hydrochloric acid that is composed of hydrogen ions and chloride ions from parietal cells in the lumen of the stomach 4. Regulation of gastric secretions – three phases: before food reaches the stomach, once the food reaches the stomach, and after food has left the stomach 5. Regulation of gastric motility and gastric emptying – use of peristalsis still occurs in the stomach; the stomach also uses electrical rhythm 6. Selected disorders of the stomach – peptic ulcer disease 7. Figures and Tables a. Figure 2.4 – structure of the stomach including a gastric gland and its secretions b. Figure 2.5 – mechanism of HCl secretion c. Figure 2.6 – approximate pHs of selected body fluids, compounds, and beverages d. Figure 2.7 – effects of selected gastrointestinal hormones/peptides on gastrointestinal tract secretions and motility D. Small Intestine 1. Chyme enters the small intestine and digestion continues with absorption of nutrients. There are three sections of the small intestine – duodenum, jejunum, and ileum 2. Key Terms a. Enterocytes – an intestinal cell b. Microvilli – extensions of intestinal epithelial cells designed to present a large surface area for absorbing dietary nutrients c. Apical – at or near the apex; pertaining to the intestinal lumen side of an enterocyte d. Glycocalyx – the layer of glycoprotein and polysaccharide that surrounds many cells

3. Structural aspects, secretions, and digestive processes of the small intestine – consists of folds of mucosa, villi, and microvilli 4. Regulation of intestinal motility and secretions – chyme is propelled by contractions that are influenced by the nervous system as well as various hormones and peptides 5. Figures and Tables a. Figure 2.8 – the small intestine b. Figure 2.9 – the structure of the small intestine c. Figure 2.10 – structure of the absorptive cell of the small intestine d. Figure 2.11 – movement of chyme in the gastrointestinal tract E. Accessory Organs 1. Pancreas – found behind the greater curvature of the stomach; contains both endocrine and exocrine cells 2. Key Terms a. Exocytosis – a process by which compounds may be released from cells b. Proteases – enzymes that digest proteins c. Serum – the pale yellowish, clear fluid portion of blood from which the clotting factors have been removed d. Acute – having a rapid or sudden onset e. Steatorrhea – the presence of an excessive amount of fat in the feces f. Enterohepatic circulation – movement of a substance, such as bile, from the liver to the intestine and then back to the liver g. Resins – compound that is usually solid or semisolid and usually exists as a polymer h. Plasma – liquid portion of blood that has been separated from the particulate portion 3. Liver – two lobes, right and left, each containing hepatocytes. Makes bile 4. Gallbladder – located on the surface of the liver; stores concentrated bile 5. Figures and Tables a. Figure 2.12 – ducts of the gallbladder, liver, and pancreas, also exocrine and endocrine portions of the pancreas b. Figure 2.13 – the anatomy of the liver c. Figure 2.14 – enterohepatic circulation of bile d. Figure 2.15 – synthesis of secondary bile acids by intestinal bacteria F. Absorptive Process 1. Absorption of most nutrients begins in the duodenum and continues throughout the jejunum and ileum. Most absorption occurs in the proximal portion of the small intestine 2. Key Terms a. Pinocytosis – process by which the plasma membrane of a cell folds inwards to ingest material b. Endocytosis – form of endocytosis in which material enters a cell through its membrane and is incorporated in vesicles for digestion c. Macronutrient – dietary nutrients that supply energy, including fats, carbohydrates, and proteins 3. Figures and Tables a. Figure 2.16 – primary sites of nutrient absorption in the gastrointestinal tract b. Figure 2.17 – primary mechanisms for nutrient absorption © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

G. Colon (Large Intestine) 1. Materials enter through the ileocecal sphincter into the cecum then through the ascending, transverse, descending, and sigmoid sections 2. Key Terms a. Microflora – bacteria adapted to living in a specific environment, such as intestines b. Fermentation – an anaerobic breakdown of carbohydrates and proteins by bacteria c. Short-chain fatty acids – fatty acids typically containing two to four carbons d. Splanchnic – pertaining to the internal organs. The splanchnic organs or portal-drained viscera include the liver, stomach, intestines, and spleen e. In vitro – in a test tube or culture f. Fermented – anaerobically broken down substrates that yield reduced products and energy g. Probiotics – products that contain specific strains of microorganisms in sufficient numbers to alter the microflora of the gastrointestinal tract, ideally to exert beneficial health effects h. Prebiotics – nondigestible food ingredients that serve as substrates to promote the colonic growth and/or activity of selected health-promoting species of bacteria 3. Colonic secretions and motility and their regulation – goblet cells secrete mucus 4. Colonic bacteria – trillions of microorganisms make up the gut microbiota 5. Figures and Tables a. Figure 2.18 – the colon b. Figure 2.19 – some benefits from the presence of bacteria in the large intestine III. Coordination and Regulation of the Digestive Process A. Neural Regulation 1. Autonomic division communicates with digestive organs directly and with the digestive tract’s own, local, nervous system B. Regulatory Peptides 1. Consists of regulatory peptides, more specifically gastrointestinal hormones and neuropeptides, that influence digestion and absorption 2. Key Terms a. Ghrelin – a hormone secreted by the stomach and duodenum that signals hunger b. Leptin – polypeptide hormone secreted by adipose tissue that reduces hunger through hypothalamic mechanisms 3. Figures and Tables a. Table 2.2 – selected regulatory hormones/peptides of the gastrointestinal tract, their main production sites, and selected digestive tract functions IV. Summary 1. The mechanisms in the gastrointestinal tract that allow food to be ingested, digested, and absorbed, are necessary for a person’s adequate nourishment and health © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Resources In-Text Web Sites The Visible Human Project In-Text Suggested Readings • Dykstra MA, Switzer NJ, Sherman V, Karmali S, Birch DW. Roux-en-Y gastric bypass: How and why it fails? Surgery Curr Res. 2014; 4:165–8. • Handzlik-Orlik G, Holecki M, Orlik B, Wylezol M, Dulawa J. Nutrition management of the post-bariatric surgery patient. Nutr Clin Prac. 2014; 29:718–39. • Mohammad AE, Elrazek AA, Elbanna AEM, Bilasy SE. Medical management of patients after bariatric surgery: Principles and guidelines. World J Gastrointest Surg. 2014; 6:220–8. • Soenen S, Rayner CK, Jones KL, Morowitz M. The ageing gastrointestinal tract. Curr Opin Clin Nutr Metab Care. 2016; 19:12–8. • Stein J, Stier C, Raab H, Weiner R. The nutritional and pharmacological consequences of obesity surgery. Aliment Pharmacol Ther. 2014; 40:582–609. • Thompson KL. Nutrition support for the critically ill, postbariatric surgery patient. Top Clin Nutr. 2014; 29:98–112. Additional Resource • Saboor, M., Zehra, A., Qamar, K., & Moinuddin. (2015). Disorders associated with malabsorption of iron: A critical review. Pakistan Journal of Medical Sciences, 31(6), 1549–1553. Disorders Associated with Malabsorption of Iron: A Critical Review

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

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Gastric bypass has become more prevalent as a treatment for obesity. However, there are many nutritional risks with the lasting effects of the procedure. What are some of these long-term effects that should be considered when making the decision to proceed or not? • Macronutrient and micronutrient deficiencies, as well as reduction/loss of intrinsic factor. Discuss the pH levels of the gastrointestinal tract and the relevance of the pH being at that level for that organ. • Most of the gastrointestinal tract is slightly alkaline, a pH around 7.8. This is to protect the organs from acidic conditions, as well as enzyme mechanisms. The stomach is at a pH of around 2.0–3.0 to aid in digestion and enzyme mechanisms but is well protected by mucus.

Assignment – Individual Project •

Digestion and absorption are processes many do not even consider when going for the first meal of the day or the delicious dinner that’s been simmering all day. There are many organs involved and many more enzymes required. Create a

diagram or process map showing how dinner enters the oral cavity and ends the digestion process in the colon. Once the organs involved are identified, add the enzymes that are being utilized within each organ and their function.

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Oral Cavity ▪ Salivary alpha-amylase – carbohydrate digestion ▪ Lingual lipase – lipid digestion Esophagus Stomach ▪ Pepsinogen – protein digestion ▪ Gastric lipase – lipid digestion Small Intestine ▪ Peptidases – protein digestion ▪ Nucleotidase – nucleotide digestion ▪ Pancreatic alpha-amylase – protein digestion ▪ Pancreatic lipase – lipid digestion ▪ Disaccharidases – carbohydrate digestion

Answer Keys Worksheet 1: Responding to Research – Malabsorption Disorders 1. a 2. a 3. cystic fibrosis; malignant lymphoma 4. Parasite infection, nutritional and/or absorption disorder, blood disorder, surgical resection. Worksheet 2: Labeling It – Transport 1. Active transport, identified by ATP being present and transport going against concentration gradient. 2. Diffusion via channel, identified by following concentration gradient (low concentration to high concentration). 3. Diffusion, identified by following concentration gradient. 4. Secondary active transport, identified by the opposite flow of Cl - and HCO3- and not the use of ATP. 5. Diffusion via channel, identified by following concentration gradient.

Worksheet 1: Responding to Research – Malabsorption Disorders Digestion is the key mechanism to your body in being able to absorb the nutrients you consume. There are many organs and processes involved in digestion, each playing a key role to the system functioning properly. If one of these key elements is altered, the entire digestion and absorption process may be altered. Read the following article and then respond to the questions. • Saboor, M., Zehra, A., Qamar, K., & Moinuddin. (2015). Disorders associated with malabsorption of iron: A critical review. Pakistan Journal of Medical Sciences, 31(6), 1549–1553. Disorders Associated with Malabsorption of Iron: A Critical Review 1. Cystic fibrosis causes the mucous to be thicker in the lungs, as well as the liver, pancreas, and small intestine. a. True b. False __________

2. Bridget has recently been suffering with severe diarrhea and pain throughout her body, especially in her knees. She is concerned if she has a disorder related to malabsorption because she has an unexpected drop in weight. Which malabsorption disorder best matches her description? a. Whipple’s disease b. Helicobacter pylori infection c. Giardiasis d. Zollinger-Ellison syndrome __________

3. An example of a disease premucosal is __________ and postmucosal is __________. a. giardiasis; malignant lymphoma b. cystic fibrosis; malignant lymphoma c. giardiasis; macroglobulinemia __________

4. Iron-deficiency anemia is usually not seen without a cause. What are a few potential causes?

Worksheet 2: Labeling It – Transport Using the figure below, label the transport that is occurring and identify how this is determined based on information provided in the figure.

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 3 – Carbohydrates Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Glucose and Ketogenic Diet Effects Worksheet 2: Nutrition Lab – Energy Yield

Chapter Outline I. Introduction 1. The major source of energy fuel in the average human diet is carbohydrate II. Overview of Structural Features 1. Carbohydrates are polyhydroxy aldehydes or ketones, or substances that produce these compounds when hydrolyzed, consisting of carbon, oxygen, and hydrogen atoms in a CH2O ratio 2. Key Terms a. Monosaccharides – the simplest form of carbohydrates, which cannot be reduced in size to smaller carbohydrate units b. Disaccharides – sugars formed by combining two monosaccharides through a glycosidic bond between the hydroxyl group of one monosaccharide and the hydroxyl group of another c. Oligosaccharides – short chains of monosaccharide units joined by covalent bonds d. Polysaccharides – long chains of monosaccharide units that may number from several to hundreds or thousands 3. Figures and Tables a. Figure 3.1 – classification of carbohydrates III. Simple Carbohydrates A. Monosaccharides 1. Contain three to seven carbon atoms and cannot be further broken down under mild hydrolytic conditions © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Key Terms a. Chiral carbon – a carbon atom with four different atoms or groups covalently attached to it b. Stereoisomers – a group of compounds that have the same structure but different configurations c. Isomers – one of two or more different chemical compounds that have the same molecular formula d. Anomeric carbon – the carbon that comprises the carbonyl function that is capable of forming a ring structure with the OH group on the highestnumbered chiral carbon of a monosaccharide 3. Ring structures – monosaccharaides do not exist in an open-chain form; instead, they form a cyclic ring structure through a reaction between the carbonyl group and a hydroxyl group 4. Haworth models – a more convenient and accurate way to represent the structures of the cyclized monosaccharides 5. Pentoses – furnish little dietary energy but are readily synthesized in the cell from hexose precursors 6. Amino and acid derivatives – amino sugars occur in oligosaccharides and polysaccharides; the amino group replaces the hydroxide group on the second carbon 7. Reducing sugars – monosaccharides that are cyclized into hemiacetals or hemiketals; capable of reducing other substances 8. Figures and Tables a. Figure 3.2 – structural formulas of the D and L configurations of glyceraldehyde b. Figure 3.3 – structural (open-chain) models of the D and L forms of the monosaccharides glucose and fructose c. Table 3.1 – various structural representations among the hexoses: glucose, galactose, and fructose B. Disaccharides 1. Contain two monosaccharide units attached to one another through acetal bonds. Maltose, lactose, sucrose, and trehalose are common disaccharides 2. Maltose – formed primarily from the partial hydrolysis of starch 3. Lactose – found naturally only in milk and milk products 4. Sucrose – most commonly used natural sweetener 5. Trehalose – found naturally in fungi and other foods of the plant kingdom 6. Figures and Tables a. Figure 3.5 – common disaccharides IV. Complex Carbohydrates A. Oligosaccharides 1. Short-chain carbohydrates. Dextrin is a common oligosaccharide B. Polysaccharides 1. Multiple repeating chains of monosaccharide residues held together with glycosidic bonds © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Key Terms a. Glycogenolysis – the pathway by which glucose is converted to glycogen 3. Starch – most common digestible polysaccharide in plants; two forms: amylose and amylopectin 4. Glycogen – major form of stored carbohydrate in animal tissues 5. Cellulose – major component of cell walls in plants 6. Figures and Tables a. Figure 3.6 – structure of starches and glycogen V. Digestion 1. Carbohydrates are hydrolyzed to monosaccharides for absorption 2. Key Terms a. Glycosidases – digestive enzymes that hydrolyze polysaccharides to their constituent monosaccharide units b. Carbohydrases – same as glycosidases B. Digestion of Polysaccharides 1. Digestion starts in the mouth with the key enzyme salivary α-amylase, a glycosidase that specifically hydrolyzes α (1-4) glycosidic linkages 2. The stomach does not digest carbohydrates and starches are further digested by pancreatic α-amylase in the small intestine 3. Figures and Tables a. Figure 3.7 – starch digestion C. Digestion of Disaccharides 1. Virtually no digestion of disaccharides or small oligosaccharides occurs in the mouth, stomach, or lumen of the small intestine. Digestion mostly happens within the microvilli in the upper small intestine via disaccharidases activity VI. Absorption, Transport, and Distribution A. Intestinal Absorption of Glucose and Galactose 1. After carbohydrate digestion, glucose and galactose are absorbed into the enterocyte by active transport and facilitated transport 2. Active transport – mechanism for glucose and galactose absorption into enterocytes requires energy as ATP and SGLT1 transporter protein 3. Facilitated transport – absorption of glucose into the enterocyte using SGLT1 without ATP 4. Figures and Tables B. Figure 3.8 – transport of monosaccharides into enterocytes using active transport and facilitated transport 1. Primary mechanism for fructose transport into the enterocyte is via facilitative transporter GLUT5 C. Post-Absorption Facilitated Transport 1. Following the intestinal absorption of glucose, galactose, and fructose, they enter the hepatic portal vein, where they are carried directly to the liver

2. Key Terms a. Hyperlipidemia – a general term for an elevated blood level of any lipid b. Erythrocytes – red blood cells D. Glucose Transporters 1. Cells depend on a continuous supply of glucose and glucose plays a central role in metabolism and cellular homeostasis. There are 14 identified glucose transport proteins, GLUT1–GLUT14 2. Key Terms a. Hyperglycemia – an above-normal blood glucose level 3. Role of insulin – GLUT4 plays an important role in the uptake of glucose 4. Figures and Tables a. Figure 3.9 – a model for the structural orientation of the glucose transporter b. Table 3.2 – glucose transporters c. Figure 3.10 – insulin signaling pathways and the translocation of GLUT4 E. Glucose Entry into Interstitial Fluid 1. Endothelial tissue is freely permeable to glucose. Epithelial layers are not readily permeable to glucose and require the use of active transport or facilitated diffusion F. Maintenance of Blood Glucose Concentration 1. Blood glucose plays a central role in homeostatic function 2. Key Terms a. Glucagon – hormone secreted by the pancreas in response to decreasing blood glucose concentration. Promotes glucose secretion by the liver, thus normalizing blood glucose concentration b. Gluconeogenesis – the formation of glucose by the liver or kidney from noncarbohydrate precursors VII. Glycemic Response to Carbohydrates A. Glycemic Index and Glycemic Load 1. Both offer a means to examine the relative risks of diets designed to control carbohydrate levels 2. Key Terms a. Glycemic index – the relative number assigned to a particular food indicating its effect on blood glucose concentration above baseline (fasting level) compared to a reference food, usually pure glucose b. Glycemic load – the glycemic load equals the glycemic index times the grams of carbohydrate in a typical portion of the food 3. Figures and Tables a. Figure 3.11 – blood glucose changes following carbohydrate intake b. Table 3.3 – glycemic index of common foods VIII.

Integrated Metabolism in Tissues 1. Key Terms a. Glycogenesis – the pathway by which glucose is converted to glycogen

b. Glycogenolysis – the pathway by which glycogen is enzymatically broken down to glucose c. Glycolysis – the pathway by which glucose is converted to pyruvate d. Gluconeogenesis – the formation of glucose by the liver or kidney from noncarbohydrate precursors e. Pentose phosphate pathway (hexose monophosphate shunt) – the pathway that metabolizes glucose-6-phosphate to pentose phosphate, producing NADPH f. Tricarboxylic acid (TCA) cycle – an aerobic metabolic cycle in the mitochondria that produces ATP; also called the citric acid cycle or Krebs cycle 2. Figures and Tables a. Figure 3.12 – integrated overview of carbohydrate metabolic pathways A. Glycogenesis 1. The pathway by which glucose is converted into its storage form glycogen 2. Key Terms a. Phosphorylation – the metabolic process of adding a phosphate group to an organic molecule 3. Figures and Tables a. Figure 3.13 – reactions of glycogenesis and primer function of glycogenin b. Table 3.4 – properties of hexokinase and glucokinase c. Figure 3.14 – formation of glycogen branches by the branching enzyme B. Glycogenolysis 1. Cleavage of glycogen into individual glucose units 2. Key Terms a. Covalent regulation – binding or unbinding of a group by a covalent bond 3. Figures and Tables a. Figure 3.15 – reactions of glycogenolysis b. Figure 3.16 – overview of the regulation of glycogen phosphorylase C. Glycolysis 1. The pathway by which glucose is degraded into two three-carbon units, pyruvate 2. Key Terms a. Substrate-level phosphorylation – the process of transferring a phosphate group from one organic molecule to another 3. Figures and Tables a. Figure 3.17 – glycolysis, indicating the mode of entry of glucose, fructose, glycogen, and galactose into glycolysis D. The Tricarboxylic Acid Cycle 1. Also called the Krebs cycle or citric acid cycle 2. Under aerobic conditions, it is the final pathway by which fuel molecules— carbohydrates, fatty acids, and amino acids—are completely oxidized to carbon dioxide and their energy is released and transferred to ATP molecules 3. Key Terms © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

a. Krebs cycle – TCA cycle 4. Conversion of pyruvate to acetyl-CoA – accomplished in the mitochondrial matrix by multienzyme complex called the pyruvate dehydrogenase complex 5. Release of high-energy electrons – TCA cycle generates high-energy electrons that are transferred to NAD+ and FAD, thus yielding NADH and FADH 6. Oxaloacetate and tricarboxylic acid cycle intermediates – to keep the TCA cycle functioning, intermediates in the form of oxaloacetate must be replenished in the cycle 7. NADH from glycolysis: the shuttle system – NADH in the cytosol is used in the lactate dehydrogenase reduction of pyruvate to lactate, becoming reoxidized to NAD+ without using oxygen 8. Figures and Tables a. Figure 3.18 – the tricarboxylic acid (TCA) cycle b. Figure 3.19 – reaction by which oxaloacetate is formed directly from pyruvate c. Figure 3.20 – glycerol-3-phosphate shuttle d. Figure 3.21 – malate-aspartate shuttle E. Formation of ATP 1. Main energy currency that must be continually synthesized from the energy provided by macronutrients through glycolysis, the TCA cycle, and the electron transport chain 2. ATP is also made through anaerobic steps. 3. Key Terms a. Dehydrogenases – enzymes that catalyze reactions in which hydrogens and electrons are removed from a reactant 4. Substrate-level phosphorylation – phosphorylation of ADP to form ATP 5. Biological oxidation and the electron transport chain – NADH and FADH2 deliver electrons and protons and are passed through a series of reactions in the electron transport chain 6. Anatomical site for the electron transport chain – hydrogen ions are transferred from within the mitochondrial matrix to the intermembrane space 7. Components of the electron transport chain and oxidative phosphorylation – uses four complexes that work independently Phosphorylation of ADP to form ATP – one glucose yields either 30 or 32 ATPs ATPs produced by complete glucose oxidation – C6H12O6 + 6O2 → 6CO2 + 6H2O + energy 8. Figures and Tables a. Table 3.5 – free energy of hydrolysis of some phosphorylated compounds b. Figure 3.22 – examples of high-energy phosphate bond being transferred from high-energy compound phosphocreatine to form ATP and the transfer of high-energy phosphate bond to a compound, allowing it to enter into the glycolytic pathway © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

c. Figure 3.23 – nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH) d. Figure 3.24 – flavin adenine dinucleotide (FAD) and its reduced form (FADH2) e. Figure 3.26 – schematic of electron transport modules connecting through coenzyme Q f. Figure 3.27 – oxidized and reduced forms of coenzyme Q or ubiquinone g. Table 3.6 – free energy changes at various sites within the electron transport chain showing phosphorylation sites h. Figure 3.28 – illustration of oxidative phosphorylation coupled with ATP synthase F. The Pentose Phosphate Pathway (Hexose Monophosphate Shunt) 1. Pathway available to glucose in the cytosol and generates important intermediates not produced in other pathways. 2. Synthesis of nucleic acids and reduced cosubstrate NADPH 3. Figures and Tables a. Figure 3.29 – the pentose phosphate pathway and the nonoxidative stage G. Gluconeogenesis 1. When blood glucose concentrations decline, hormones including glucagon trigger glycose synthesis from noncarbohydrate sources 2. Key Terms a. Cori cycle – metabolic pathway in which lactate is released into the bloodstream and transported to the liver where the lactate is converted to glucose by gluconeogenesis; glucose is released into the bloodstream and taken up by muscle and red blood cells were it can enter glycolysis, thus completing the cycle 3. Figures and Tables a. Figure 3.30 – the principal regulatory mechanisms in glycolysis and gluconeogenesis b. Figure 3.31 – reactions of gluconeogenesis IX. Regulation of Metabolism A. Allosteric Enzyme Modulation 1. This mechanism can stimulate or suppress the enzymatic activity of a pathway 2. AMP, ADP, and ATP as allosteric modulators – each modulate energy breakdown and production 3. Regulatory effect of NADH/NAD+ – regulate their own formation through negative modulation B. Covalent Regulation 1. This type of pathway regulation is done by the binding or unbinding of a group by a covalent bond C. Genetic Regulation

1. This enzyme regulation is done through genetics by inducing transcription of new messenger RNA; also can induce or suppress expression of a gene through hormone regulation D. Directional Shifts in Reversible Reactions 1. Control mechanism for pathways based on enzyme kinetics, the concentration of the reactants and products in the cell E. Metabolic Control of Glycolysis and Gluconeogenesis 1. Most enzymatic reactions are reversible, yet in a given cell and generally in the cells of a particular organ the pathways are going in only one direction at a given time 2. Figures and Tables a. Figure 3.32 – insulin-independent and -dependent pathways of glucose metabolism X. Summary 1. This chapter teaches the vital importance in nutrition: the release and conversion of the energy contained within nutrient molecules into ATP energy that is usable by the body

Resources In-Text Web Sites • National Library of Medicine • Medscape • WebMD – Provides specialty information and education for physicians and other health professionals • Centers for Disease Control and Prevention • American Medical Association • Virtual Cell Animation Collection – A series of “Virtual Cell” animations demonstrating electron transport chain, ATP synthesis, insulin signaling, and other biological processes; funded by the National Science Foundation. Other animations are applicable to other chapters and are good resources. • Johns Hopkins School of Medicine Additional Resource o

Pliss, L., Jatania, U., & Patel, M. S. (2016). Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency. Molecular Genetics and Metabolism Reports, 7, 78–86. Article ID Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. • Transporter proteins aid the cells in getting energy substrates across the membrane. What are five different glucose transporter proteins and where are they expressed? • GLUT1 – erythrocytes, central nervous system, blood-brain barrier, placenta, and fetal tissues • GLUT2 – liver, β-cells of pancreas, kidney, and small intestine • GLUT3 – neurons, spermatozoa, placenta, preimplantation embryos • GLUT4 – muscle, heart, brown and white adipocytes • GLUT5 – Intestine, kidney, brain, skeletal muscle, adipose tissue • GLUT6 – brain, spleen, and peripheral leukocytes • GLUT7 – small intestine and colon • GLUT8 – testis, brain, adrenal gland, liver, spleen, brown adipose tissue, and lung • GLUT9 – not known • GLUT10 – heart, lung, brain, liver, skeletal muscle, pancreas, placenta, and kidney • GLUT11 – not known • GLUT12 – skeletal muscle, small intestine, heart, and prostrate • GLUT13 – brain, adipose tissue, and kidney • GLUT14 – testis • Discuss the gross production of ATP and the net production of ATP during glycolysis. • The gross production of ATP during glycolysis is four ATP molecules. However, phosphorylation requires one molecule of ATP and the conversion of fructose requires another, yielding a net total of two ATP molecules being produced during glycolysis

Assignment – Individual Paper •

The electron transport chain is the process within cellular respiration that yields many ATP molecules. This process involves different complexes. Each of these complexes is at risk for malfunctioning. Find a disorder that affects one of either Complex I, Complex II, Complex III, or Complex IV process. Explain the complex’s role in energy production, where it is located in the process, the symptoms the disorder causes, and if there is a treatment and what that is for the disorder. Complex I Deficiency • Role: NADH-Coenzyme Q Oxidoreductase • Location: first step in electron transport chain in mitochondria • Disorder: NADH dehydrogenase deficiency ▪ LHON ▪ MELAS ▪ MERRF ▪ Leigh syndrome

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Symptoms: myopathy, mitochondrial encephalomyopathy, fatal infantile multisystem disorder Treatments: no cure ▪ Metabolic therapies including: riboflavin, thiamine, biotin, co-enzyme Q10, carnitine ▪ Ketogenic diet

Complex II Deficiency • Role: Succinate Dehydrogenase • Location: second step in electron transport chain in mitochondria • Disorder: Succinate dehydrogenase deficiency ▪ May cause Leigh syndrome • Symptoms: mitochondrial encephalomyopathy ▪ Failure to thrive ▪ Developmental delay ▪ Hypotonia ▪ Lethargy ▪ Respiratory distress ▪ Ataxia ▪ Myoclonus ▪ Lactic acidosis • Treatments: same as complex I Complex III Deficiency • Role: Coenzyme Q-Cytochrome c Oxidoreductase • Location: third step in the electron transport chain in the mitochondria • Disorder: Ubiquinone-cytochrome c oxidoreductase deficiency • Symptoms ▪ Fatal infantile encephalomyopathy • Congenital lactic acidosis, hypotonia, dystrophic posturing, seizures, coma ▪ Encephalomyopathies of later onset • Weakness, short stature, ataxia, dementia, hearing loss, sensory neuropathy, pigmentary retinopathy, pyramidal signs ▪ Myopathy • Weakness, ragged red fibers, lactic acidosis ▪ Infantile histiocytic cardiomyopathy Complex IV Deficiency • Role: Cytochrome c Oxidase • Location: fourth step in the electron transport chain in the mitochondria • Disorder: Cytochrome c oxidase deficiency • Symptoms ▪ Encephalomyopathy: Early in life, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, dystonia, pyramidal signs, respiratory distress ▪ Myopathy

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Early in life, hypotonia, weakness, lactic acidosis, ragged red fibers, respiratory distress

Answer Keys Worksheet 1: Research Study – Glucose and Ketogenic Diet Effects 1. b 2. d 3. increased; X-linked 4. Stabilization of brain lesions, and more normal plasma carnitine levels when the ketogenic diet is introduced shortly after birth. Worksheet 2: Nutrition Lab – Energy Yield 1. 3:2 ratio 2. 32 ATP molecules 3. 384 kilocalories 4. 32 ATP molecules  384 kilocalories  1000 calories = 12,288,000 calories

Worksheet 1: Research Study – Glucose and Ketogenic Diet Effects Cellular respiration requires many steps that increase the chances of a mutation within one of the processes. The ketogenic diet has proven to be beneficial in aiding in the control of many disorders, especially those dealing with energy production and use. It is a diet high in fat and low in carbohydrates, and requires education on following the diet correctly. Read the following article and then respond to the questions. o Pliss, L., Jatania, U., & Patel, M. S. (2016). Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency. Molecular Genetics and Metabolism Reports, 7, 78–86. Article ID Beneficial effect of feeding a ketogenic diet to mothers on brain development in their progeny with a murine model of pyruvate dehydrogenase complex deficiency 1. The ketogenic diet should not be used because the brain requires glucose for energy. If the ketogenic diet is used, then the individual starves the brain of the necessary glucose. a. True b. False __________ 2. Sally needs to start eating a ketogenic diet immediately. She is 4 years old and her family is needing recommendations of which type of foods Sally should eat. Which answer fits the ketogenic diet the best? a. Many fruits and vegetables. b. Lean meats with green leafy vegetables. c. A balanced standard diet, eliminating sweets. d. Many oils and long-chain fatty acids. __________ 3. Males are at a/an __________ risk for mortality when diagnosed with pyruvate dehydrogenase complex deficiency due to the disease being __________. a. decreased; X-linked b. decreased; autosomal recessive c. increased; X-linked __________ 4. What clinical improvements have ketogenic diets shown?

Worksheet 2: Nutrition Lab – Energy Yield 1. What is the ratio of ATP molecules produced to NADH/FADH2?

2. How many molecules of ATP are produced from each molecule of glucose?

3. How many kilocalories are in each molecule of ATP?

4. How many calories are gained following four cycles of cellular respiration?

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 4 – Fiber Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Responding to Research – Fiber in the Maternal Diet Worksheet 2: Labeling It – Chemical Structures of Fibers

Chapter Outline I. Introduction 1. Fiber enhances health of the gastrointestinal tract and plays many key roles in the prevention and management of several diseases II. Definitions 1. Definitions for dietary, functional, and total fiber were established in 2002 through the publication of Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Protein, and Amino Acids by the National Academy of Sciences Food and Nutrition Board 2. Key Terms a. Dietary fiber – nondigestible (by human digestive enzymes) carbohydrates and lignin that are intact and intrinsic in plants b. Functional fiber – nondigestible carbohydrates that have been isolated, extracted, or manufactured and have been shown to have beneficial physiological effects in humans c. Total fiber – the sum of dietary fiber plus functional fiber that is in a food III. Fiber and Plants 1. Fiber is found in plant foods 2. Figures and Tables a. Figure 4.1 – the partial anatomy of a wheat plant b. Figure 4.2 – dietary fibers and some of their selected properties IV. Chemistry and Characteristics of Fiber A. Cellulose 1. Dietary fiber and functional fiber; long, linear polymer 2. Key Terms a. Polymer – a substance with a high molecular weight, made up of a chain of repeating units © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. Figures and Tables a. Figure 4.3 – chemical structures of dietary fibers and some functional fibers B. Hemicellulose 1. Dietary fiber consisting of a heterogeneous group of polysaccharides C. Pectins 1. Dietary and functional fiber, representing another family of heterogeneous polysaccharides found in plant cell walls, intercellular regions of plants, and in the outer skin and rind of some fruits and vegetables D. Lignin 1. Highly branched polymer of phenol units with strong intramolecular bonding E. Gums 1. Also called hydrocolloids; secreted at the site of plant injury by specialized secretory cells 2. Key Terms a. Exudates – fluids that have exuded (been forced or pressed) out of a tissue or its capillaries F. β-Glucans 1. Homopolymers of glucose units, but smaller in size and contain different linkages than cellulose G. Fructans 1. Sometimes called polyfructose; include inulin, oligofructose, and fructooligosaccharides H. Resistant Starch 1. This is starch that cannot be or is not easily enzymatically digested I. Mucilages (Psyllium) 1. Mucilages are plant polysaccharides with a structure similar to gums J. Polydextrose and Polyols 1. Polydextrose is a polysaccharide consisting of glucose and sorbitol units that have been polymerized at high temperatures and under a partial vacuum K. Resistant Dextrins 1. These are also called resistant maltodextrins and are generated by heating and enzymatically treating starch, usually cornstarch or wheat starch L. Chitin and Chitosan 1. Chitin is a straight-chain polymer containing β (1-4)-linked glucose units, similar to cellulose, but with an N-acetyl amino group. Chitosan is a deacetylated form of chitin 2. Figures and Tables a. Table 4.1 – food sources of fiber V. Selected Properties of Fibers and Their Physiological Impact A. Solubility in Water 1. Water-soluble fibers are those that dissolve in hot water, whereas insoluble fibers do not dissolve in hot water B. Viscosity and Gel Formation 1. Viscosity is related to the fiber’s ability both to bind or hold water and to form a gel within the digestive tract © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

C. Fermentability 1. Fiber reaches the colon undigested by human digestive enzymes. The colonic bacteria then ferment the undigested fiber 2. Figures and Tables a. Figure 4.4 – selected gastrointestinal responses to fiber ingestion VI. Health Benefits of Fiber A. Cardiovascular Disease 1. Ingestion of diets high in fiber is associated with a reduced risk of death from cardiovascular disease B. Diabetes Mellitus 1. Inverse associations between dietary fiber intake and risk of developing type 2 diabetes have been demonstrated in several studies C. Appetite and/or Satiety and Weight Control 1. Fiber-rich foods tend to have a lower energy density and a higher volume, which can promote satiety D. Gastrointestinal Disorders VII. Low fiber intake has been linked to three disorders: constipation, diverticular disease, and colon cancer. Irritable bowel syndrome has been linked with consumption of specific fibers VIII. Food Labels and Health Claims A. Nutrient recommendations for fiber, as well as other nutrients, are found on the Nutrition Facts panel on food labels IX. Recommended Fiber Intake A. Recommendations for increasing the amount of fiber in the U.S. diet have come from several government agencies and private organization. The Dietary Guidelines suggest that Americans ingest 14 g of fiber per 1,000 kcal B. Figures and Tables 1. Table 4.2 – recommended fiber intakes 2. Table 4.3 – dietary fiber content of selected foods X. Summary A. This chapter provides a brief review of the basics of a cell, including cellular components, biological energy, and an overview of a cell’s natural life span

Resources In-Text Suggested Readings • Asano T, McLeod RS. Dietary fibre for the prevention of colorectal adenoma and carcinomas. Cochrane Database Syst Rev. 2002; CD003430. • Ben Q, Sun Y, Chai R, Qian A, Xu B, Yuan Y. Dietary fiber intake reduces risk for colorectal adenoma: a meta-analysis. Gastroenterology. 2014; 146:689–99. • Eswaran S, Muir J, Chey WD. Fiber and functional gastrointestinal disorders. Am J Gastroenterol. 2013; 108:718–27.

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Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2014; 37:S120–43.

Additional Resource • Chu, D. M., Antony, K. M., Ma, J., Prince, A. L., Showalter, L., Moller, M., & Aagaard, K. M. (2016). The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Medicine, 8, 77. Article ID The early infant gut microbiome varies in association with a maternal high-fat diet

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

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Fiber has been shown to provide health benefits. What are some health benefits of fiber in cardiovascular disease and prevention? • Shown to lower LDL cholesterol, reductions in cholesterol absorption and bile reabsorption through trapping bile acids and cholesterol within fiber’s gelatinous mass. Fiber has been shown to provide health benefits. What are some health benefits of fiber in diabetes mellitus disease and prevention? • Diets high in fiber have shown improved glycemic control. Reductions of insulin secretion due to slower glucose absorption in the blood.

Assignment – Individual Paper •

As you have learned through this chapter, fiber plays a very important role in your digestive health and overall health. Based on your daily dietary intake, calculate the amount of fiber you need, explain the need, and design a three-day meal plan to include this necessary fiber intake and sources. • Fiber intake is recommended to be 14 g per 1,000 kcal consumption. Recommended fiber sources are described in Table 4.3. Based on the student’s daily kcal consumption, determine how many grams of fiber the student needs.

Answer Keys

Worksheet 1: Responding to Research – Fiber in the Maternal Diet 1. b 2. b 3. lipids; fibers 4. Answer: Limit sugars. Increase their consumption of proteins and lipids. Worksheet 2: Labeling It – Chemical Structures of Fiber 1. Cellulose; β (1-4)-linked glucose units 2. Hemicellulose; β (1-4)-linked D-xylopyranose units with branches of 4-O-methyl Dglucopyranose uronic acids linked by α (1-2) bonds of L-arabinofuranosyl units linked by α (1-3) bonds 3. Gums; β (1-3) linkages and β (1-6) linkages 4. β-glucan; mostly β (1-4) linkages, but also β (1-3) linkages

Worksheet 1: Responding to Research – Fiber in the Maternal Diet Fiber plays a key role in digestion, as well as overall health. It also is suggested to play an important role in the maternal diet. The maternal diet highly affects the pregnant mother as well as the developing fetus. Read the following article and then respond to the questions. • Chu, D. M., Antony, K. M., Ma, J., Prince, A. L., Showalter, L., Moller, M., & Aagaard, K. M. (2016). The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Medicine, 8, 77. Article ID The early infant gut microbiome varies in association with a maternal high-fat diet 1. Consuming the recommended dietary fiber in maternal diets has shown to reduce the chances of developing gestational diabetes. a. True b. False __________

2. Cayce has recently learned she is pregnant. She currently has type 2 diabetes and is very worried about developing gestational diabetes. She wants to take every precaution she may to prevent the disorder. What is the best recommendation? a. Start consuming additional fiber through supplements. b. Speak with your nutritionist to get a balanced diet with the recommended daily dietary fiber intake. c. Reduce your carbohydrate intake to limit the amounts of sugars consumed, including fiber. d. Speak with your physician about beginning the ketogenic diet. __________

3. A maternal diet high in __________ has shown to affect the offspring microbiome, but ___________ have not shown to affect the offspring microbiome. a. fibers; carbohydrates b. carbohydrates; lipids c. lipids; fibers __________

4. Do maternal mothers, diagnosed with gestational diabetes, need to limit in their diets? What types of macronutrients should they consume then to keep their recommended kcal diets?

Worksheet 2: Labeling It – Chemical Structures of Fibers Using the figures below, identify the type of fiber that comprises the structure and the bond structure of the fiber. 1.

1. _______________; _______________ 2. _______________; _______________ 3. _______________; _______________ 4. _______________; _______________ © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 5 – Lipids Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Nutrition Label Worksheet 2: Nutrition Lab – Palmitic Acid ATP Yield

Chapter Outline I. Introduction 1. This chapter covers the structures of lipids, importance, dietary sources, digestion, absorption, transport and storage, and disease related to lipids 2. Lipids are one of the macromolecules required for the body 3. Key Terms a. Eicosanoids – biologically active substances derived from linoleic and αlinolenic essential fatty acids b. Sterols – a subclass of lipids that contains a cyclopentanoperhydrophenanthrene ring system, a hydroxyl group, and a side chain c. Phospholipids – lipids that belong to a class of lipids containing phosphate and one or more fatty acid residues d. Sphingolipids – class of lipids that contain the amino alcohol sphingosine as a backbone structure, with a fatty acid attached to the amino group II. Structure and Biology Importance A. Fatty Acids 1. Simplest of the lipids. Composed of a hydrocarbon chain with a methyl group at one end and a carboxylic acid group at the other; they are polar with a hydrophilic end and a nonpolar hydrophobic end 2. Key Terms a. Desaturation – the process of converting a saturated compound to an unsaturated one b. Elongation – (1) the extension of the polypeptide chain of the protein product during protein synthesis. (2) the addition of carbons to a fatty acid chain

3. Fatty acid nomenclature – two systems of notation developed a. delta (∆) system of notation denotes the chain length of the fatty acids and the number and position of any double bonds present b. notation locates the position of double bonds on carbon atoms counted from the methyl end of the hydrocarbon chain 4. Essential fatty acids – two unsaturated fatty acids cannot be synthesized in the body and must come from the diet. These are linoleic acid and αlinolenic acid 5. N-6 versus n-3 fatty acids – intake of n-3 fatty acids is quite low compared to the overwhelmed intake of n-6 fatty acids 6. Figures and Tables a. Figure 5.1 – structures of selected fatty acids b. Figure 5.2 – structure of linoleic acid, showing two system for nomenclature c. Table 5.1 – some naturally occurring fatty acids d. Table 5.2 – fatty acid composition of fats and oils B. Triacylglycerols (Triglycerides) 1. Most adipose tissue composed of triacylglycerols, which are a highly concentrated form of stored energy 2. Figures and Tables a. Figure 5.3 – linkage of fatty acids to glycerol to form a triacylglycerol. Chain length of fatty acids is (n+2) C. Phospholipids 1. These are lipids that form the structural basis of all cell membranes, including membrane of organelles within the cell. These are more polar than triacylglycerols and sterols 2. Key Terms a. Amphipathic – refers to a molecule that has a polar region at one location and a nonpolar region at another 3. Biological roles of phospholipids – amphipathic nature and attract water molecules a. Found on surface of blood – borne lipoprotein particles b. Important components of cell and organelle membranes and form the bilayer c. Physiologically active compounds d. Aid in anchoring membrane proteins when the proteins are covalently attached to lipids 4. Figures and Tables a. Figure 5.4 – typical structure of phospholipids b. Figure 5.5 – structure of diphosphatidylglycerol c. Figure 5.6 – inositol dual signaling system D. Sphingolipids 1. Found in the plasma membrane of all cells, with highest concentration in the central nervous system; have sphingolipids built on the amino alcohol sphingosine rather than glycerol as the structural backbone 2. Key Terms a. Sphingomyelin – sphingolipid containing phosphocholine at the terminal hydroxyl

b. Cerebrosides – sphingolipids containing a single galactose or glucose unit at the terminal hydroxyl c. Gangliosides – sphingolipids containing an oligosaccharide at the terminal hydroxyl, with sialic acid attached to the oligosaccharide chain 3. Figures and Tables a. Figure 5.7 – structure of sphingolipids E. Sterols 1. Have a four-ring steroid nucleus and at least one hydroxyl group. Three categories: cholesterol, bile acids, and phytosterols 2. Cholesterol – most common in humans, important constituent of plasma membranes due to its amphipathic nature 3. Bile acids and bile salts – critical components of bile that act as detergents in the small intestine to emulsify dietary lipids for digestion and absorption 4. Phytosterols – structurally similar to cholesterol; found throughout the food supply 5. Figures and Tables a. Figure 5.8 – structure of a sterol, cholesterol, and cholesterol ester b. Figure 5.9 – formation of physiologically important steroids from cholesterol c. Figure 5.10 – formation of glycocholate, taurocholate, glycochenodeoxycholate, and taurochenodeoxycholate-conjugated bile acids III. Dietary Sources A. Recommended Intakes 1. Recommended intakes come from several governmental and nongovernmental organizations, including the American Heart Association, the Institute of Medicine, the U.S. Department of Agriculture, and the U.S. Department of Health and Human Services 2. The Food and Nutrition Board of the Institute of Medicine has not established a Recommended Dietary Allowance (RDA) for total fat intake 3. Adequate Intake (AI) levels have been established for infants, but not for adults or children over the age of 12 months 4. Figures and Tables a. Figure 5.11 – dietary fat contribution from major food groups b. Table 5.3 – fat content of common foods IV. Digestion A. Triacylglycerol Digestion 1. Most triacylglycerol digestion is completed in the lumen of the small intestine. The process begins in the mouth and stomach with lingual lipase released by the serous gland, which lies beneath the tongue, and gastric lipase produced by chief cells of the stomach 2. The role of colipase – colipase is formed by hydrolytic activation of trypsin of procolipase 3. Figures and Tables a. Table 5.4 – overview of triacylglycerol digestion B. Phospholipid Digestion

1. Phospholipids are hydrolyzed by a specific esterase, phospholipase A2, made and secreted by the pancreas C. Cholesterol Ester Digestion 1. Some of the cholesterol present in food is esterified with a fatty acid. Cholesterol esters cannot be absorbed and therefore must be hydrolyzed to free cholesterol and free fatty acid to be incorporated into micelles for delivery to intestinal cells 2. Figures and Tables a. Figure 5.12 – summary of digestion and absorption of dietary lipids V. Absorption A. Fatty Acid, Monoacylglycerol, and Lysophospholipid Absorption 1. Two general mechanisms of absorption of fatty acids, monoacylglycerols, and lysophospholipids have been suggested; one involves a proteinindependent diffusion model and another a protein-dependent model B. Cholesterol Absorption 1. Cholesterol that enters the small intestine comes from two sources: the diet and bile 2. Key Terms a. Chylomicrons – a type of lipoprotein that transports lipids and lipidsoluble vitamins from the intestine into the lymph and then the blood for use by body cells C. Lipid Release into Circulation 1. Lipids that are esterified in the endoplasmic reticulum of the enterocytes are assembled into large lipid-protein aggregate structures, chylomicrons 2. Key Terms a. Apolipoprotein – the protein component of a lipoprotein particle VI. Transport and Storage 1. Key Terms a. Lipoproteins – complexes of lipids and proteins that play a role in the transport and distribution of lipids A. Lipoprotein Structure 1. Hydrophobic, nonpolar neutral lipids reside in the spherical core, surrounded by a monolayer of amphipathic phospholipids and free cholesterol that partitions the neutral lipid from the aqueous environment 2. Figures and Tables a. Figure 5.13 – generalized structure of a plasma lipoprotein b. Table 5.5 – apolipoproteins of human plasma lipoproteins c. Figure 5.14 – lipid and protein of lipoprotein classes B. Lipoprotein Metabolism 1. Main function of lipoproteins is to transport lipids in the blood 2. Key Terms a. Chylomicron remnants – the portion of a chylomicron that is left after blood lipoprotein lipase removes part of its triglycerides 3. Exogenous lipid transport – exogenous lipids are packaged immediately into chylomicrons within the enterocyte and distributed to peripheral tissues, mainly muscle and adipose tissue

4. Endogenous lipid transport – hepatic triacylglycerols are packaged in VLDL and delivered to peripheral tissues in a manner similar to chylomicrons 5. Reverse cholesterol transport – ability of circulating HDL to pick up excess cholesterol from peripheral tissues and deliver it to the liver for excretion from the body via bile, as either free cholesterol or bile acids 6. Figures and Tables a. Figure 5.15 – exogenous lipid transport b. Figure 5.16 – lipid metabolism in the adipose cell following a meal c. Figure 5.17 – metabolism in the liver following a fatty meal d. Figure 5.18 – endogenous lipid transport e. Figure 5.19 – sequential steps in endocytosis of LDL leading to synthesis and storage of cholesterol ester f. Figure 5.20 – reverse cholesterol transport VII. Lipids, Lipoproteins, and Cardiovascular Disease Risk A. Cholesterol 1. Cholesterol is a major component to atherogenic fatty plaque, and many studies have linked CVD risk to chronically elevated serum cholesterol levels B. Saturated and Unsaturated Fatty Acids 1. Findings from older research studies led to the conclusions that saturated fatty acids are hypercholesterolemic, polyunsaturated fatty acids are hypocholesterolemic, and monounsaturated fatty acids are neutral C. Trans Fatty Acids 1. Dietary trans fatty acids may be more unfavorable than saturated fatty acids because they raise LDL-C and lower HDL-C. They also correlate more strongly with cardiovascular disease mortality than saturated fatty acids D. Lipoprotein(a) 1. Composed of a low-density lipoprotein particle containing apoB-100 and a covalently linked glycoprotein called apolipoprotein E. Apolipoprotein E 1. Apolipoprotein E has multiple roles in lipid metabolism, neurobiology, and cellular function VIII. Integrated Metabolism in Tissues A. Catabolism of Triacylglycerols and Fatty Acids 1. Triacylglycerols stored in adipose tissue are mobilized by lipase-catalyzed hydrolysis and released into circulation as free fatty acids when needed 2. Mitochondrial transfer of acyl–CoA-activated fatty acid is joined covalently to carnitine at the cytosolic side of the outer mitochondrial membrane by the transferase enzyme carnitine acyltransferase I, the carnitine: acylcarnitine transferase then moves acyl-carnitine across the inner membrane. Acyl-carnitine is then released to form acyl-CoA and carnitine with the aid of carnitine acyltransferase II 3. β-oxidation of fatty acids – this occurs through a cyclic degradative pathway by which two-carbon units in the form of acetyl-CoA are cleaved, one acetyl-CoA at a time from the carboxyl end 4. Energy yield in fatty acid oxidation – net yield of ATPs is 106 5. Figures and Tables © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

a. Figure 5.22 – membrane transport system for transporting fatty acyl-CoA across the inner mitochondrial membrane b. Figure 5.23 – the mitochondrial β-oxidation of an activated fatty acid using palmitate as an example c. Figure 5.24 – sequential β-oxidation of oleic acid d. Figure 5.25 – oxidation of propionyl-CoA B. Formation of Ketone Bodies 1. Concentration of ketone bodies in the blood is usually low but will increase in situations of accelerated fatty acid oxidation 2. Key Terms a. Ketone bodies – compounds formed during the oxidation of fatty acids in the absence of adequate four-carbon intermediates b. Ketogenesis – process of producing ketone bodies c. Ketosis – condition resulting in elevated ketone body concentration in the blood d. Ketoacidosis – blood acidosis due to excessive ketone bodies 3. Figures and Tables a. Figure 5.26 – steps in hepatic ketone body formation C. Synthesis of Fatty Acids 1. Involves the synthesis of all fatty acids from acetyl-CoA besides linoleic acid and α-linolenic acid 2. Key Terms a. Thromboxanes – biologically active compounds derived from linoleic or αlinolenic acids b. Leukotrienes – biologically active compounds derived from linoleic or αlinolenic acids c. Signal-lipidomics – a branch of the emerging field of lipidomics, which studies the pathways and networks of cellular lipids. These studies involves polyunsaturated fatty acids such as docosahexaenoic acid 3. Essential fatty acids – linoleic acid and α-linolenic acid are essential fatty acids and must be obtained from the diet 4. Eicosanoids: fatty acid derivatives of physiological significance – when eicosanoids are synthesized, the polyunsaturated fatty acid precursors are mobilized from the phospholipids or triacylglycerols by phospholipase A2 5. Opposing effects of n-6 and n-3 fatty acid-derived eicosanoids – most arachidonic acid-derived messengers are pro-inflammatory or show other disease-propagating effects, whereas n-3 derivatives oppose these effects 6. Impact of diet on fatty acid synthesis – following a carbohydrate-rich meal, de novo fatty acid synthesis increases mainly in the liver and in many other tissues 7. Figures and Tables a. Figure 5.27 – formation of malonyl-CoA from acetyl-CoA and CO2 b. Figure 5.28 – loading of sulfhydryl groups into the fatty acid synthase system c. Figure 5.29 – steps in the synthesis of fatty acid d. Figure 5.30 – polyunsaturated fatty acid biosynthesis e. Table 5.6 – n-3 and n-6 fatty acid-derived messengers and their physiological effects D. Synthesis of Triacylglycerols and Phospholipids © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

1. Triacylglycerols and phospholipids share common precursors, which are CoA-activated fatty acids and glycerol-3-phosphate 2. Figures and Tables a. Figure 5.31 – a schematic summary of the synthesis of triacylglycerols and lecithin showing that precursors are shared E. Synthesis, Catabolism, and Whole-Body Balance of Cholesterol 1. Cholesterol is not an energy-containing nutrient and is not required in the diet since it can be synthesized 2. In mammals, no degradative enzymes exist, so cholesterol catabolism depends on its conversion to other molecules and its elimination from the body through biliary excretion 3. Figures and Tables a. Figure 5.32 – an overview of the pathway of cholesterol biosynthesis in the hepatocyte indicating the negative regulatory effect of cholesterol on the HMG-CoA reductase reaction IX. Regulation of Lipid Metabolism A. Fatty Acids 1. Linked to carbohydrate status, synthesis increases when adequate carbohydrates are consumed, whereas oxidation increases in carbohydrate deficit B. Cholesterol 1. The liver is the central organ responsible for maintaining cholesterol homeostasis X. Brown Fat Thermogenesis A. Brown adipose tissue is metabolically active, and greater abundance in the neck area of adults is associated with lower adiposity; contributes to increasing energy expenditure and insulin sensitivity B. Key Terms 1. Thermogenesis – production of heat within the body C. Figures and Tables 1. Figure 5.33 – a schematic of the inner membrane of a mitochondrion from brown adipose tissue showing uncoupling protein 1, the components of the electron transport chain, and ATP synthase XI. Ethyl Alcohol: Metabolism and Biochemical Impact A. Alcohol Dehydrogenase (ADH) Pathway 1. ADH is a soluble enzyme functioning in the cytosol of hepatocytes; oxidizes ethanol to acetaldehyde 2. Figures and Tables a. Figure 5.34 – ethanol oxidation in hepatocytes B. Microsomal Ethanol Oxidizing System (MEOS) 1. MEOS is able to oxidize a wide variety of compounds in addition to ethanol, including fatty acids, aromatic hydrocarbons, steroids, and barbiturate drugs; the oxidation is mediated by cytochrome P450 enzyme, CYP2E1, and involves a system of electron transport C. Catalase System

1. The enzyme catalase is located in peroxisomes, and in the presence of hydrogen peroxide, is capable of oxidizing ethanol to acetaldehyde D. Alcoholism: Biochemical and Metabolic Alterations 1. Caused by an excessive consumption of ethanol with consequences of fatty liver, hepatic disease, lactic academia, and metabolic tolerance 2. Acetaldehyde toxicity – acetaldehyde is a product of ethanol oxidation, which is believed to have direct adverse effects on the metabolic system 3. High NADH:NAD+ ratio – oxidation of ethanol increases the concentration of NADH at the expense of NAD+ 4. Substrate competition – deficiency of vitamin A is usually seen with excessive alcohol metabolism 5. Induced metabolic tolerance – ethanol can induce enzymes of the MEOS, causing an increased rate of metabolism of substrates oxidized by this system 6. Figures and Tables a. Figure 5.35 – reduction of dihydroxyacetone phosphate to glycerol-3-P, producing NAD+ from NADH b. Figure 5.36 – reversible reaction of glutamate and NAD+ forming αketoglutarate, NADH, and ammonia, catalyzed by glutamate dehydrogenase E. Alcohol in Moderation: The Brighter Side 1. Positive effects of alcohol or wine intake on oxidative stress, insulin insensitivity, diabetes mellitus, and inflammation have been shown XII. Summary A. The hydrophobic character of lipids makes them special among the macronutrients B. Fatty acids are a rich source of energy, and lipids provide much energy C. Too many lipids can lead to health consequences and diseases

Resources In-Text Web Sites • Diet and Health – Food and Nutrition Information Center of the National Agricultural Library (U.S. Department of Agriculture) • American Heart Association – Provides dietary recommendations for reducing risk of cardiovascular diseases • Eat Right – Academy of Nutrition and Dietetics. Provides dietary and exercise recommendations for all age groups In-Text Suggested Readings • Wang W, Zhu J, Lyu F, et al. v-3 polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer. Prostaglandins Other Lipid Mediat. 2014; 113–115:13–20. • Maehre HK, Jensen IJ, Elvevoll EO, Eilertsen KE. v-3 fatty acids and cardiovascular diseases: effects, mechanisms and dietary relevance. Int J Mol Sci. 2015; 18:22636–61.

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Excellent reviews highlighting the metabolic role of n-3 fatty acids, including their benefits and limitations in disease prevention. Resnik D. Trans fat bans and human freedom. Am J Bioeth. 2010; 10:27-32. Lichtenstein AH. New York City trans fat ban: improving the default option when purchasing foods prepared outside of the home. Ann Intern Med 2012; 157:144–5. Downs SM, Thow AM, Leeder SR. The effectiveness of policies for reducing dietary trans fat: a systematic review of the evidence. Bull World Health Organ 2013; 91:262H–269H.

Additional Resource • Schneeman, B. (2015). Science-based regulatory and policy considerations in nutrition. Advances in Nutrition, 6(3), 361S–367S. Article ID Science-based regulatory and policy considerations in nutrition

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. • Trans fats are hidden all over in our diets. Discuss which foods we can find these fats in and ways to eliminate them in our diets. • Trans fats are found in many bakery items, oils, popcorns, chips, cookies, and other snack items. They can be eliminated by using oils that do not contain these trans fats, making our own bakery goods avoiding trans fats, and watching the nutrition label very carefully. • Ethanol is an indulgence for many. What are some benefits of consuming ethanol, but restricting the amount? • Positive effects have been seen with oxidative stress, insulin insensitivity, diabetes, and inflammation.

Assignment – Individual Paper •

Refer to Table 5.6 and discuss the importance of a balanced diet in both n-3 fatty acids and n-6 fatty acids. What are the benefits? What are the derived messengers and their effects? • Prostaglandins ▪ N-6 pro-arrhythmic ▪ N-3 anti-arrhythmic • Thromboxanes ▪ N-6 platelet activator and vasoconstriction ▪ N-3 platelet inhibitor and vasodilator • Leukotrienes ▪ N-6 pro-inflammatory ▪ N-3 anti-inflammatory • Epoxyeclosatrienoic derivatives ▪ N-6 pro-inflammatory • Hydroxyleicosatetraenoic derivatives • Lipoxins • Resolvins

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▪ N-3 anti-inflammatory Neuroprotection ▪ N-3 anti-inflammatory

Answer Keys Worksheet 1: Responding to Research – Nutrition Label 1. b 2. a 3. 2000; less 4. Read the nutrition label but also pay attention to the ingredient list. Many ingredients are listed under different names, so educate yourself on the different possibilities. Worksheet 2: Nutrition Lab – Palmitic Acid ATP Yield 1. 3  7  1.5 = 31.5 2. 3  7  2.5 = 52.5 3. 3  8  10 = 240 4. 31.5 + 52.5 + 240 = 324, then 324 – 6 = 318 Net ATPs

Worksheet 1: Research Study – Nutrition Label What goes on the nutrition label is regulated by the FDA. Due to this, many individuals do not even know that they are consuming different fats because when they read the nutrition label and it states zero grams they no know different. The truth is in the list of ingredients. Read the following article and then respond to the questions. • Schneeman, B. (2015). Science-based regulatory and policy considerations in nutrition. Advances in Nutrition, 6(3), 361S–367S. Article ID Science-based regulatory and policy considerations in nutrition 1. Even if there is 0.1 grams of trans fat in a food, it must show that amount on the nutrition label. a. True b. False __________ 2. Prior to approval of a health claim on food packaging, the FDA raises concerns. Which is not one of those concerns? a. Did the study verify results using an animal model? b. Did those involved in the study know which study group they belonged to or was it blinded? c. How was the protocol verified? d. What methods were used to measure intake and effects? __________ 3. Nutrition labels are based on a __________ calorie diet. Many should consume __________ calories. a. 2500; more b. 2500; less c. 2000; less __________ 4. What are some ways to know exactly what you are consuming?

Worksheet 2: Nutrition Lab – Palmitic Acid ATP Yield You have three 16-carbon palmitic acid molecules that need to undergo oxidation. 1. What is the total ATP yield from FADH2?

2. What is the total ATP yield from NADH?

3. What is the total ATP yield from acetyl-CoA?

4. What is the net yield of ATPs?

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 6 – Protein Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Responding to Research – mTOR and Asparagine Worksheet 2: Labeling It – Amino Acid Metabolism

Chapter Outline I. Introduction 1. This chapter covers the vitality of protein consumption in the diet. Proteins are essential because of their constituent amino acids. This chapter focuses on protein classification, sources, digestion, absorption, use, and changes throughout aging II. Amino Acid Classification A. Structure 1. General structure of an amino acid contains an amino group, a central carbon, one carboxyl group, and a side chain 2. Figures and Tables a. Table 6.1 – Structural classification of amino acids B. Net Electric Charge 1. Amino acids in an aqueous solution are ionized. Will migrate toward the cathode if placed in an electrical field 2. Key Terms a. Zwitterion – a dipolar ion that has both negatively and positively charged regions, such as an amino acid. The ion has no net charge in solution C. Polarity 1. The tendency of an amino acid to interact with water at physiological pH. This depends on the side chain of the amino acid. 2. Polar-charged amino acids interact with aqueous and can form salt bridges; neutral amino acids interact with water at varying degrees; nonpolar amino acids do not interact with water 3. Figures and Tables a. Table 6.2A – neutral amino acids b. Table 6.2B – amino acids exhibiting a net charge c. Table 6.2C – polar and nonpolar amino acids

D. Essentiality 1. Nine essential amino acids – meaning that the body needs them from the diet 2. Five conditionally indispensable amino acids – meaning that the body may need them from the diet depending on the availability of their precursor(s) 3. Figures and Tables a. Table 6.2D – essential/indispensable amino acids b. Table 6.2E – conditionally indispensable amino acids and their precursors III. Sources of Amino Acids 1. Amino acids are derived from protein, both dietary and endogenous IV. Digestion 1. Figures and Tables a. Figure 6.1 – an overview of protein digestion b. Table 6.3 – major enzymes responsible for protein digestion B. Stomach 1. Protein digestion begins in the stomach with the action of hydrochloric acid 2. Pepsin hydrolyzes interior peptide bonds within proteins. End products following protein digestion in the stomach are polypeptides, some oligopeptides, and free amino acids 3. Key Terms a. Endopeptidase – an enzyme that hydrolyzes amino acids linked to other amino acids in the interior of a peptide or protein C. Small Intestine 1. Chyme – nutrient mixture stimulates the release of regulatory hormones and peptides such as secretin and cholecystokinin 2. Key Terms a. Proteolytic – pertaining to the breakdown of protein b. Exopeptidases – an enzyme that hydrolyzes amino acids off the terminal end of a peptide or protein c. Dipeptidyl aminopeptidase – a protein-digesting enzyme that breaks apart dipeptides V. Absorption A. Intestinal Cell Absorption 1. Key Terms a. Hartnup disease – a hereditary disorder in which tryptophan absorption and excretion are abnormal 2. Amino acid absorption across the intestinal brush border membrane – most amino acids are absorbed in the duodenum and jejunum 3. Paracellular absorption via passage through the tight junctions of enterocytes or transcellular endocytosis can occur 4. Peptide absorption across the intestinal brush border membrane – peptide transport across the brush border membrane of the enterocyte is accomplished by a transport system different from those that transport amino acids, known as PEPT1

5. Amino acid absorption across the intestinal basolateral membrane – amino acids are transported across the basolateral membrane of the enterocyte and into interstitial fluid, where they enter the blood through capillaries of the villi for transport into the portal vein 6. Defects in amino acid absorption – genetic mutations prevent the synthesis of functional transporters needed for amino acid transport 7. Figures and Tables a. Table 6.4 – some systems transporting amino acids across the intestinal cell brush border membrane b. Figure 6.2 – sodium-dependent transport of an amino acid into a cell c. Figure 6.3 – peptide transport d. Table 6.5 – some systems transporting amino acids across the intestinal cell basolateral membrane B. Extraintestinal Cell Absorption 1. After amino acids are transported out of the enterocyte, they enter portal blood and are transported to tissues 2. Figures and Tables a. Figure 6.4 – the γ-glutamyl cycle for transport of amino acids VI. Amino Acid Catabolism A. Transamination of Amino Acids 1. Frequently, the first step in amino acid catabolism is the transfer or removal of an amino acid’s amino group 2. Figures and Tables a. Figure 6.5 – transamination reactions B. Deamination of Amino Acids 1. These reactions involve only the removal of an amino group from an amino acid, with no transfer of the amino group to another compound 2. Key Terms a. Deamination – the removal of an amino group from an amino acid 3. Figures and Tables a. Figure 6.6 – deamination of the amino acid threonine C. Disposal of Ammonia 1. Ammonia is generated by deamination reactions, but also found through chemical reactions, deamination of the amide groups from glutamine and asparagine, ingestion and absorption of foods, and bacterial lysis 2. Glutamate and glutamine synthesis – glutamate dehydrogenase readily uses an ammonia or ammonium ion and α-ketoglutarate to make the amino acid glutamate 3. Urea cycle – functions in the liver and removes ammonia 4. Figures and Tables a. Figure 6.7 – interrelationships of amino acids and the urea and TCA/Krebs cycles in the liver D. Carbon Skeleton/α-Keto Acid Uses 1. The remaining portion once an amino group has been removed from an amino acid 2. Energy production – complete oxidation of amino acids generates energy

3. Glucose production – production of glucose from a noncarbohydrate source such as amino acids is known as gluconeogenesis; occurs primarily in the liver 4. Ketone body production – catabolism of the amino acid generates acetylCoA or acetoacetate, which are used for the formation of ketone bodies 5. Cholesterol production – oxidation of several amino acids, including isoleucine, leucine, lysine, tryptophan, and threonine, yields acetyl-CoA, which can be metabolized to produce cholesterol 6. Fatty acid production – in times of excess energy and protein intakes, coupled with adequate carbohydrate intake, the carbon skeleton of amino acids may be used to synthesize fatty acids 7. Figures and Tables a. Figure 6.8 – possible fates of amino acids upon catabolism b. Figure 6.9 – fate of amino acid carbon skeletons E. Hepatic Catabolism and Uses of Aromatic Amino Acids 1. Amino acid catabolism occurs in most body tissues, especially liver, for aromatic and sulfur-containing amino acids 2. Phenylalanine and tyrosine – catabolized to acetoacetate and are partially ketogenic and partially glucogenic. Phenylketonuria (PKU) is an autosomal recessive genetic disorder that affects the metabolism of phenylalanine to tyrosine 3. Tryptophan – metabolized mostly in the liver, partially glucogenic. αketoadipic aciduria results from defective activity of α-ketoadipic dehydrogenase 4. Figures and Tables a. Figure 6.10 – phenylalanine and tyrosine metabolism b. Figure 6.11 – tryptophan metabolism F. Hepatic Catabolism and Uses of Sulfur (S)-Containing Amino Acids 1. Metabolism of S-containing amino acids occurs mainly in the liver 2. Methionine – glucogenic amino acid via its oxidation generates the TCA cycle intermediate, succinyl-CoA. Disorders in methionine adenosyl transferase results in hypermethioninemia 3. Cysteine – nonessential amino acid 4. Figures and Tables a. Figure 6.12 – methionine and cysteine metabolism G. Hepatic Catabolism and Uses of Branched-Chain Amino Acids 1. Liver plays a minor role in initial catabolism of isoleucine, leucine, and valine H. Hepatic Catabolism and Uses of Basic Amino Acids 1. Lysine – ketogenic amino acids generate acetyl-CoA following catabolism. Defects in lysine degradation by glutaryl-CoA dehydrogenase and αketoadipate dehydrogenase result in glutaric aciduria type 1 and αketoadipic aciduria 2. Arginine – metabolized mostly in the liver and kidneys; glucogenic amino acid, and its catabolism generates the TCA cycle intermediate αketoglutarate 3. Histidine – gluconeogenic amino acid yielding α-ketoglutarate 4. Figures and Tables a. Figure 6.13 – lysine metabolism © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

b. Figure 6.14 – arginine, proline, histidine, and glutamate metabolism I. Hepatic Catabolism and Uses of Other Selected Amino Acids 1. Threonine – three different metabolism pathways and is both glucogenic and ketogenic. Defects lead to propionic academia and methylmalonic academia 2. Glycine and serine – can be produced from one another in a reversible reaction, catalyzed by vitamin B6. Impaired glycine metabolism results in nonketotic hyperglycinemia 3. Figures and Tables a. Figure 6.15 – threonine, glycine, and serine metabolism b. Figure 6.16 – summary of the uses of selected amino acids for synthesis of nitrogen-containing compounds and selected biogenic amines, hormones, and neuromodulators VII. Protein Synthesis A. Slow versus Fast Proteins 1. Fast proteins include whey protein, soy protein, amino acid mixtures, and protein hydrolysates; an example of slow proteins is casein B. Plant versus Animal Proteins 1. Plant-based protein sources typically are limiting in one or more essential amino acids, most often methionine and/or lysine, and have lower digestibility compared to animal-based protein C. Hormonal Effects 1. During prolonged fast, such as overnight, protein synthesis still occurs but at a much lower rate. Epinephrine, cortisol, glucagon, insulin, and other hormones all affect protein synthesis D. Amino Acids, Intracellular Signaling, and mTOR 1. mTOR is a large protein kinase complex that functions as part of a signaling pathway; able to stimulate and mediate the effects of insulin and leucine E. Protein Intake, Distribution and Quantity at Meals 1. Muscle protein synthesis over a 24-hour period appears to be greater with consistent consumption of protein at each meal VIII.

Protein Structure and Organization 1. Proteins begin to fold and take shape as they are synthesized on the ribosomes 2. Figures and Tables a. Figure 6.17 – primary structure of a protein b. Figure 6.18 – secondary structure of proteins c. Figure 6.19 – tertiary structure of protein α-lactalbumin d. Figure 6.20 – quaternary structure of hemoglobin protein

IX. Functional Role of Proteins and Nitrogen-Containing Nonprotein Compounds A. Catalysts 1. Enzymes that change the rate of reactions B. Messengers 1. Hormones that act as chemical messengers in the body 2. Key Terms © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

a. Hormones – chemical messengers synthesized and secreted by endocrine tissue and transported in the blood to target tissues or organs C. Structural Elements 1. Contractile proteins and fibrous proteins; two main contractile proteins are actin and myosin; fibrous proteins include collagen, elastin, and keratin D. Buffers 1. Help regulate acid-base balance 2. Key Terms a. Buffer – a compound that meliorates a change in pH 3. Figures and Tables a. Figure 6.21 – the role of the amino acid in pH balance E. Fluid Balancers 1. Proteins help attract and keep water inside a particular area and contribute to osmotic pressure 2. Key Terms a. Osmotic pressure – a property of a solution that is proportional to the nondiffusible solute concentration F. Immunoprotectors 1. Five major classes produced by the plasma cells derived from Blymphocytes 2. Key Terms a. Immunoproteins – proteins made by plasma cells that help destroy foreign substances in the body G. Transporters 1. Provide means of carrying substances 2. Key Terms a. Transport proteins – proteins that transport nutrients in blood or into and out of cells or cell organelles H. Acute-Phase Responders 1. Made in the liver and respond to acute, critical illnesses and injury I. Other Roles 1. Transmit signals, intestinal barrier regulation, cell junctions 2. Key Terms a. Glycoproteins – proteins covalently bound to a carbohydrate J. Nitrogen-Containing Nonprotein Compounds 1. Not proteins but play important roles in the body 2. Key Terms a. Tolerable upper intake level – the highest daily intake level that is likely to cause no risk of adverse health effects to most individuals in the general population 3. Glutathione – tripeptide synthesized from three amino acids—glycine, cysteine, and glutamate 4. Carnitine – made from amino acid lysine that has been methylated 5. Creatine – key component of the energy compound creatine phosphate, and synthesis begins with glycine and arginine 6. Carnosine – made from histidine and β-alanine in an energy-dependent reaction catalyzed by carnosine synthetase

7. Choline – made primarily in the liver through the methylation of the phospholipid phosphatidylethanolamine when linked with the catabolism of phosphatidylcholine 8. Purine and pyrimidine bases – pyrimidine bases are uracil, cytosine, and thymidine (single ring); the purine bases are adenine and guanine (two fused rings) 9. Figures and Tables a. Table 6.6 – sources of nitrogen for some nitrogen-containing nonprotein compounds b. Figure 6.22 – structure of glutathione in its reduced form c. Figure 6.23 – carnitine synthesis d. Figure 6.24 – creatine synthesis and use e. Figure 6.25 – carnosine f. Figure 6.26 – choline g. Figure 6.27 – initial reactions of pyrimidine synthesis h. Figure 6.28 – formation of the pyrimidine nucleoside triphosphates UTP, CTP, and TTP for DNA and RNA synthesis i. Figure 6.29 – pyrimidine and purine ring structure and bases j. Figure 6.30 – synthesis of inosine monophosphate k. Figure 6.31 – formation of purines and nucleoside triphosphates needed for DNA and RNA synthesis l. Figure 6.32 – degradation of purines AMP and GMP generates uric acid X. Interorgan Flow of Amino Acids and Organ-Specific Metabolism A. Intestinal Cell Amino Acid Metabolism 1. Uses structural proteins, nucleotides, apoproteins, enzymes, hormones, and nitrogen-containing compounds to use amino acids for energy production as well as for synthesis of proteins and nitrogen-containing compounds 2. Intestinal glutamine metabolism – provides a primary source of energy and trophic effects 3. Intestinal glutamate metabolism – arises from the diet or glutamine metabolism, often transaminated with pyruvate to form α-ketoglutarate and alanine. Alanine enters the portal blood for transport to the liver 4. Intestinal aspartate metabolism – occurs within the intestinal cells; undergoes transamination to generate oxaloacetate 5. Intestinal arginine metabolism – used by intestinal cells yielding citrulline and urea 6. Intestinal methionine (and cysteine) metabolism – methionine is also metabolized by intestinal cells and cysteine generated from methionine or obtained directly in the diet and is used to make glutathione 7. Figures and Tables a. Figure 6.33 – partial overview of amino acid metabolism in the intestinal cell B. Amino Acids in the Plasma 1. Amino acid concentrations typically rise in the plasma for several hours following ingestion of protein and the return to basal concentrations C. Glutamine and the Muscle, Intestine, Liver, and Kidneys 1. Glutamine has many roles in the body, one being ammonia transport © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Key Terms a. Alkalosis – a condition in which the pH of the blood is higher than approximately 7.45, the upper end of the normal range 3. Figures and Tables a. Figure 6.34 – some pathways of glutamine generation in muscle D. Alanine and the Liver and Muscle 1. Alanine is important in the intertissue transfer of amino groups generated from amino acid catabolism 2. Figures and Tables a. Figure 6.35 – alanine-glucose cycle E. Skeletal Muscle Use of Amino Acids 1. Uptake of amino acids by the skeletal muscles readily occurs following ingestion of food, especially protein 2. Isoleucine, leucine, and valine catabolism – muscles, heart, kidneys, diaphragm, adipose tissue, and other organs possess branched-chain aminotransferases and aid in the transamination of all three branchedchain amino acids; defects affecting the branched-chain amino acids can result in abnormal plasma concentrations, acidosis, dehydration, neurological problems, seizures, coma, and mental retardation 3. Indicators of muscle mass and muscle/protein catabolism – changes in plasma amino acid concentrations do not reflect changes in muscle mass, instead using creatinine and 3-methylhistidine as indicators of existing muscle mass and muscle degradation 4. Figures and Tables a. Figure 6.36 – branched-chain amino acid metabolism F. Amino Acid Metabolism in the Kidneys 1. Includes glutamine catabolism, glycine catabolism, serine synthesis, arginine and glycine use, glutathione catabolism, arginine syntheses, tyrosine synthesis, and histidine generation 2. Figures and Tables a. Figure 6.37 – amino acid metabolism in selected organs b. Table 6.7 – nitrogen-containing waste products excreted in the urine G. Brain and Accessory Tissues and Amino Acids 1. Uses active transport for amino acids and has transport systems for neutral, basic, and acidic amino acids 2. Neurotransmitters and biogenic amines – several amino acids act directly as neurotransmitters, such as glycine, taurine, aspartate, and glutamate 3. Neuropeptides – small protein-like compounds that are similar to neurotransmitters but have more diverse effects 4. Other metabolic roles of amino acids outside of neuropeptides, biogenic amines, and neurotransmitters in the brain and nervous system 5. Figures and Tables a. Figure 6.38 – GABA synthesis from the amino acid glutamate b. Figure 6.39 – serotonin synthesis and degradation c. Figure 6.40 – structures of the catecholamines

XI. Catabolism of Tissue Proteins and Protein Turnover 1. Key Terms a. Autophagy – the breakdown or digestion of the body’s proteins, such as those found in the blood or within cells B. Lysosomal Degradation 1. Found in all mammalian cells, except red blood cells, and act like cellular garbage digestive system to degrade proteins, nucleic acids, lipids, and carbohydrates, among other compounds 2. Key Terms a. Cathepsins – a group of enzymes involved in breaking down or digestion of the body’s proteins C. Proteasomal Degradation 1. Can also degrade proteins 2. Key Terms a. Calpains – a calcium-dependent protease involved in protein turnover in the body 3. Figures and Tables a. Figure 6.41 – proteasomal degradation of a protein XII.

Changes in Body Mass with Age 1. Body composition is influenced by gender, race, heredity, stature, and age. Throughout aging, fat is gained and muscle is lost 2. Figures and Tables a. Table 6.8 – body composition of reference man and woman

XIII.

Protein Quality and Protein and Amino Acid Needs 1. Key Terms a. Complete protein – a protein that contains all the essential amino acids in the approximate amounts needed by humans b. Incomplete proteins – a dietary protein source that is missing or contains insufficient amounts of one or more indispensable amino acids needed for protein synthesis in the body c. Limiting amino acid – the amino acid within a protein with the lowest amino acid or chemical score; it is the amino acid present in a protein in the lowest amount, compared with a reference amount 2. Figures and Tables a. Table 6.9 – incomplete protein-containing foods and their limiting amino acids B. Evaluation of Protein Quality 1. Several methods available 2. Protein digestibility corrected amino acid score – a score used to indicate protein quality 3. Digestible indispensable amino acid score – used to assess protein quality 4. Protein efficiency ratio – represents body weight gained on a test protein divided by the grams of protein consumed 5. Chemical or amino acid score – involves determination of the amino acid composition of a test protein

6. Biological value – used to assess protein quality, a measure of how much nitrogen is retained in the body for maintenance and growth rather than absorbed 7. Net protein utilization – measures protein quality, similar to nitrogen balance studies, is net protein utilization 8. Net dietary protein calories percentage – used to evaluate diets in the protein-to-calorie ratio; varies greatly 9. Figures and Tables a. Table 6.10 – amino acid scoring/reference patterns and whole-egg pattern b. Table 6.11 – amino acid scoring/reference patterns used for regulatory purposes C. Protein Information on Food Labels 1. Food labels must indicate the amount of protein in grams and the % Daily Value for protein in a serving of food D. Assessing Protein and Amino Acid Needs 1. Nitrogen balance and amino acid oxidation are used to assess the adequacy of protein and amino acid intakes 2. Nitrogen balance/nitrogen status – involve the evaluation of dietary nitrogen intake and the measurement and summation of nitrogen losses from the body 3. Indicator amino acid oxidation – method involves feeding test amino acids individually to a person in graded amounts in the presence of an indicator amino acid E. Recommended Protein and Amino Acid Intakes 1. Requirements are influenced by age, body size, and physiological state, as well as level of energy intake 2. Figures and Tables a. Figure 6.42 – recommended dietary allowances for indispensable amino acids for adults F. Protein Deficiency/Malnutrition 1. Assessment of malnutrition includes identification of inflammation, evidence of reduced dietary intake, unintended weight loss, loss of subcutaneous fat, loss of muscle, localized or generalized fluid accumulation, and reduced physical functional status 2. Key Terms a. Marasmus – malnutrition caused by prolonged intake of a diet deficient in energy XIV.

Summary 1. Proteins are available in foods and are broken down by the body into amino acids; nine are essential, with eleven that are nonessential 2. The amino acids are used for synthesis of new proteins, production of nonprotein nitrogen-containing compounds, oxidation for energy, and synthesis of glucose, ketones, or fatty acids

Resources In-Text Suggested Readings • Finnerty CC, Mabvuure NT, Ali A, Kozar RA, Herndon DN. The surgically induced stress response. JPEN. 2013; 37:21S–29S. • Parlato M. Host response biomarkers in the diagnosis of sepsis: a general overview. Methods Molec Biol. 2015; 1237:149–211. • Watt DG, Horgan PG, McMillan DC. Routine clinical markers of the magnitude of the systemic inflammatory response after elective operation: a systemic review. Surgery. 2015; 157:362–80. Additional Resource • Krall, A. S., Xu, S., Graeber, T. G., Braas, D., & Christofk, H. R. (2016). Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nature Communications, 7, 11457. Article ID. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

•

What are the differences between polar and nonpolar amino acids and what is the role of polarity in amino acids? • It is the difference between whether an amino acid will interact with water. It all depends on the side chain of the amino acid. The polarity dictates which environments they will interact in. What are the two types of absorption involved in amino acid absorption? Describe each. • Intestinal cell absorption and extraintestinal cell absorption. Intestinal cell absorption happens along the entire small intestine and extraintestinal cell absorption is when the amino acids are transported out of the enterocyte, entering the portal blood, and transported to the tissues

Assignment – Individual Paper •

Draw and compare the different structures of protein. • Primary ▪ Single chain of amino acids • Secondary ▪ α-helix and β-pleated sheets • Tertiary ▪ Three-dimensional structure of folding of α-helices and β-pleated sheets • Quaternary ▪ Three-dimensional subunits

Answer Keys Worksheet 1: Responding to Research – mTOR and Asparagine 1. a 2. b 3. c. non-polar amino acids 4. Once the cell is glutamine-independent, they require exogenous supply of the amino acid asparagine. Worksheet 2: Labeling It – Amino Acid Metabolism 1. Tyr in the brain/kidney/blood 2. Gln in the brain/muscle/blood/kidney 3. Asp in the muscle/blood/kidney 4. Ala in the muscle/blood/kidney

Worksheet 1: Responding to Research – mTOR and Asparagine mTOR is a large protein kinase that is a primary variant in oncology studies, development studies, and mutation studies. However, it is not well-known to most. This might be your first time ever learning about mTOR. mTOR regulates cell proliferation. Read the following article and then respond to the questions. • Krall, A. S., Xu, S., Graeber, T. G., Braas, D., & Christofk, H. R. (2016). Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nature Communications, 7, 11457. Article ID. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor 1. The amino acid asparagine levels impact the proliferation of cancer cells. a. True b. False __________

2. How does asparagine regulate mTOR? a. Through its exchange with serine b. Through its regulation of arginine c. By knocking down mTOR expression d. Through its regulation of threonine __________

3. Asparagine prefers to exchange with the amino acid serine because asparagine prefers __________. a. charged amino acids b. polar amino acids c. nonpolar amino acids __________

4. How do cancer cells continue to grow following glutamine independence?

Worksheet 2: Labeling It – Amino Acid Metabolism Using the figure below, fill in the missing amino acids and discuss if they are metabolized elsewhere in the body.

1. _______________ 2. _______________ 3. _______________ 4. _______________

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 7 – Integration and Regulation of Metabolism and the Impact of Exercise Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Starvation Worksheet 2: Nutrition Lab – Starvation Effects

Chapter Outline I. Introduction 1. This chapter covers the chemical reactions taking place and the pathways being followed during metabolism to maintain homeostasis of the body 2. Key Terms a. Exercise – planned, structured physical activity to enhance physical fitness II. Energy Homeostasis in the Cell 1. Figures and Tables a. Figure 7.1 – metabolic pathways involved in the maintenance of energy homeostasis B. Regulatory Enzymes 1. These enzymes aid in the regulation of catabolism and anabolism; found at strategic points in metabolic pathways 2. Role of malonyl-CoA – plays a role in both fatty acid synthesis and βoxidation. Its regulatory role is expressed through its allosteric control of carnitine acyltransferase I 3. Role of AMP – activated protein kinase that serves as a master energy sensor, controlling both catabolic and anabolic pathways involving all the macronutrients 4. Figures and Tables a. Table 7.1 – cellular energy status, metabolic response, and allosteric control sites b. Figure 7.2 – role of malonyl-CoA in fatty acid synthesis and oxidation III. Integration of Carbohydrate, Lipid, and Protein Metabolism A. Interconversion of Fuel Molecules

1. Balance between catabolism and anabolism both short term and long term, including all macronutrients and their products 2. Key Terms a. Amphibolic pathway – a pathway that is involved in both the catabolism and the biosynthesis of carbohydrates, fatty acids, and/or amino acids B. Energy Distribution among Tissues 1. Metabolism in every tissue is unique and markedly different 2. Liver – most nutrients absorbed by the small intestine first pass through the liver, and many fuel molecules released by extrahepatic tissues travel to the liver for additional processing 3. Muscle – fatty acids and glucose are the major fuels for both skeletal and cardiac muscle 4. Adipose tissue – stores huge amounts of triacylglycerols and is an energy reservoir for the body 5. Brain – glucose is the primary fuel used by the brain and nerve cells 6. Red blood cells – rely exclusively on glucose as their only energy source under all metabolic conditions 7. Kidneys – require about 10% of the total energy used by the body and function to produce urine and remove metabolic waste products from the blood plasma 8. Figures and Tables a. Figure 7.3 – pathways of glucose-6-phosphate metabolism in the liver b. Figure 7.4 – pathways of amino acid metabolism in the liver c. Figure 7.5 – pathways of fatty acid metabolism in the liver IV. The Fed-Fast Cycle A. Fed State 1. Is the disposition of glucose, fat, and amino acids among the major tissues 2. Figures and Tables a. Figure 7.6 – disposition of dietary glucose, amino acids, and triacylglycerols in the fed state B. Postabsorptive State 1. With the onset of this state, tissues can no longer derive energy directly from ingested macronutrients, but instead must begin to depend on fuel sources already in the body 2. Figures and Tables a. Figure 7.7 – distribution of fuel molecules in the postabsorptive state C. Fasting State 1. After 18–48 hours of no food intake, in the liver gluconeogenesis increases in wake of hepatic glycogen depletion 2. Figures and Tables a. Figure 7.8 – distribution of fuel molecules in the fasting state b. Figure 7.9 – interchanges of selected amino acids and their metabolites among body organs and tissues D. Starvation State 1. If fasting state persists and progresses, a more dramatic metabolic fuel shift occurs 2. Figures and Tables a. Figure 7.10 – distribution of fuel molecules in the starvation state © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

b. Table 7.2 – fuel metabolism in starvation c. Figure 7.11 – changes in plasma concentration of fuel molecules following a single meal V. Hormonal Regulation of Metabolism 1. Figures and Tables a. Table 7.3 – hormonal regulations of energy metabolism B. Insulin 1. Major anabolic hormone that impacts glucose, fatty acids, and protein synthesis and storage. Secreted by the β-cells of the pancreas in response to rising blood glucose; half-life of 4–6 minutes C. Glucagon 1. The metabolic responses elicited by glucagon oppose those of insulin. Is secreted by the α-cells of the pancreas when blood glucose levels decline; half-life in circulation of 3–6 minutes D. Epinephrine 1. A catecholamine produced in the adrenal medulla from the amino acids phenylalanine and tyrosine; functions both as neurotransmitter in the nervous system and a stress hormone in circulation E. Cortisol 1. Produced in the adrenal cortex from cholesterol and released in response to low blood glucose levels; half-life of 1 hour F. Growth Hormone 1. Also known as somatotropin; produced by the anterior pituitary gland; halflife of 12–16 minutes; secreted in response to fasting and strenuous exercise VI. Exercise and Nutrition A. Muscle Function 1. Main proteins in muscle are actin and myosin; upon stimulation, myosin ATPase hydrolyzes ATP that provides the energy for muscle contraction. Myoglobin can store oxygen B. Energy Sources in Resting Muscle 1. Even at rest, energy is needed to maintain basal function that includes active transport, replenishing glycogen and triacylglycerol stores, and continuous synthesis and breakdown of proteins 2. Energy needs are met primarily by oxidation of fatty acids and glucose C. Muscle ATP Production during Exercise 1. Contracting muscle fibers require ATP via three energy systems: ATPphosphocreatine system, lactic acid system, and oxidative system 2. ATP-phosphocreatine system – uses high-energy phosphate bond of phosphocreatine to quickly regenerate ATP 3. Lactic acid system – uses the glycolytic pathway anaerobically to produce ATP through substrate phosphorylation by the incomplete breakdown of one molecule of glucose into two molecules of lactate in skeletal muscle 4. Oxidative system – involves the TCA cycle and oxidative phosphorylation to completely catabolize glucose, fatty acids, and some amino acids to CO 2 and H2O

5. Figures and Tables a. Figure 7.12 – relative contribution of energy systems during the onset of exercise D. Fuel Sources during Exercise 1. Exercise intensity and duration – skeletal muscles utilize mostly glucose and fatty acids, but will use amino acids if needed 2. Fatigue – muscle fatigue occurs when the supply of glucose is inadequate 3. Benefits of exercise training – endurance training increases the ability to perform more aerobically at the same absolute exercise intensity 4. Carbohydrate loading (supercompensation) – this is a dietary and exercise strategy to maximize the storage of glycogen in muscle and liver for the purpose of enhancing endurance performance 5. Figures and Tables a. Figure 7.13 – utilization of fuel sources after 30 minutes of exercise at different exercise intensity b. Figure 7.14 – utilization of fuel sources during prolonged exercise at 65– 75% VO2 max c. Figure 7.15 – schematic representation of the classical and modified regimens of muscle glycogen supercompensation VII.

Summary 1. The human body must maintain and adjust in response to the energy status of cells, tissues and organs, and the whole body

Resources In-Text Suggested Readings • Brown WMC, Davison GW, McClean CM, Murphy MH. A systematic review of the acute effects of exercise on immune and inflammatory indices in untrained adults. Sports Med. 2015; 1:35. • The article reviews the transient changes in immune and inflammatory markers evoked by a single bout of exercise and the resulting health benefits, including reduced risk of cardiovascular disease. • McArdle WD, Katch FL, Katch VL. Exercise Physiology: Nutrition, Energy, and Human Performance. 8th ed. Baltimore: Wolters Kluwer, 2015. • A textbook that provides in-depth coverage of the metabolic principles connecting nutrition, muscle function, energy metabolism, and exercise performance. • Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1a, myokines and exercise. Bone. 2015; 80:115–25. • A review article that describes the regulatory molecules secreted by exercising muscle and their metabolic impact on health. Additional Resource • Elliott, B., Mina, M., & Ferrier, C. (2016). Complete and Voluntary Starvation of 50 days. Clinical Medicine Insights. Case Reports, 9, 67–70. Article ID Complete and Voluntary Starvation of 50 days

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. • You are running a 10K next weekend. What fuel sources will be used, when, and what does it depend on? • After 30 minutes, energy is derived from the plasma glucose, plasma-free fatty acid, muscle triacylglycerol, and muscle glycogen. • You have your 10-year class reunion next weekend and you want to lose 10 pounds for it. You hate exercising, so you have decided to starve yourself for 3 or 4 days. Will this work? What will happen? • It will not work because your body will start regulating metabolism. During the starvation period, ketone bodies will increase, glucose will drop, and fatty acids will slowly increase.

Assignment – Individual Paper •

Draw and fill in a comparison table that shows the energy distribution among tissues. • Liver ▪ Most nutrients absorbed by the small intestine first pass through the liver, and many fuel molecules released by extrahepatic tissues travel to the liver for additional processing. • Muscle ▪ Fatty acids and glucose are the major fuels for both skeletal and cardiac muscle. • Adipose tissue ▪ Stores huge amounts of triacylglycerols and is an energy reservoir for the body. • Brain ▪ Glucose is the primary fuel used by the brain and nerve cells. • Red blood cells ▪ Rely exclusively on glucose as their only energy source under all metabolic conditions. • Kidneys ▪ Require about 10% of the total energy used by the body and function to produce urine and remove metabolic waste products from the blood plasma.

Answer Keys Worksheet 1: Responding to Research – Starvation 1. b 2. d 3. a gain 4. body has been depending on ketone bodies for energy, gastrointestinal organs have only been digesting liquids with no nutritional value, and the energy distribution has been changed in all organs © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

Worksheet 2: Labeling It – Nutrition Lab – Starvation Effects 1. Glucose; 100 to 40, glucose consumption is limited, glucose is not available for absorption 2. Ketone bodies; 50 to 100, since glucose is not readily available, fatty acids are being used for ketone production 3. Muscle protein degradation; 75 to 20, amino acids are not readily available in the diet, so the focus is on the energy going to the brain 4. Ketone bodies; 150 to 150, liver continues to use fatty acids for the production of ketones

Worksheet 1: Responding to Research – Starvation Many individuals are not happy with their body sizes. They find themselves either too overweight, too thin, not muscular enough, or too muscular. Some take it too extreme with their health and decide to starve themselves. This isn’t the healthiest option available. Read the following article and then respond to the questions. • Elliott, B., Mina, M., & Ferrier, C. (2016). Complete and Voluntary Starvation of 50 days. Clinical Medicine Insights. Case Reports, 9, 67–70. Article ID Complete and Voluntary Starvation of 50 days 1. Starvation is safer and causes the body to lose weight faster than eating a lowercalorie, well-balanced diet combined with exercise. a. True b. False __________ 2. Starvation can leave lasting effects. Which is not a risk to starvation? a. cardiovascular complications b. elevation of bilirubin c. change in gastrointestinal organs’ sizes and functions d. celiac disease __________ 3. Following starvation when eating is resumed, this tends to lead to __________ of weight. a. continued loss b. a gain c. maintenance __________ 4. Following the starvation period, the subject began eating liquids. Why not resume solid foods first?

Worksheet 2: Nutrition Lab – Starvation Effects Using the table and figure below, fill in the missing pieces and explain why there is the change in levels during starvation between day 3 and day 40.

1. 2. 3. 4.

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 8 – Energy Expenditure, Body Composition, and Healthy Weight Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Metabolic Syndrome in Adolescents Worksheet 2: Nutrition Lab – Body Mass Index and Effects

Chapter Outline I. Introduction 1. The body is constantly using energy 2. When the amount of energy consumed equals what is used, the person is in energy balance 3. Key Terms a. Energy balance – when the amount of food energy matches energy expenditure over time II. Measuring Energy Expenditure A. Direct Calorimetry 1. A way to measure the amount of energy being used by the body; uses sensible heat loss and heat of water vaporization 2. Key Terms a. Direct calorimetry – method of measuring the dissipation of heat from the body B. Indirect Calorimetry 1. A way to measure the amount of energy being used by the body; heat released by metabolic oxidation is calculated indirectly measuring oxygen consumption 2. Key Terms a. Indirect calorimetry – measurement of the consumption of oxygen and the expiration of carbon dioxide by the body; used to estimate metabolic rate b. Respiratory quotient – ratio of the volume of carbon dioxide expired to the volume of oxygen consumed © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. RQ and substrate oxidation – an RQ equal to 1.0 suggests that carbohydrate is being oxidized because the amount of oxygen required for the combustion of glucose equals the amount of carbon dioxide produced 4. RQ and energy expenditure – once the RQ has been calculated, the calculation of energy expenditure is performed using the caloric value of oxygen at different RQ values 5. Figures and Tables a. Figure 8.1 – a portable device to measure oxygen consumption and carbon dioxide production b. Figure 8.2 – a metabolic cart measures oxygen consumption and carbon dioxide exhaled c. Table 8.1 – thermal equivalent of O2 and CO2 for nonprotein RQ C. Doubly Labeled Water 1. Isotopes equilibrate throughout the water compartments in the body over about 5 hours III. Components of Energy Expenditure 1. Key Terms a. Thermoregulation – process whereby a regulatory mechanism keeps heat production and loss about equal 2. Figures and Tables a. Figure 8.3 – components of energy expenditure and their approximate percentage contribution B. Basal and Resting Metabolic Rate 1. This is the amount of energy needed to sustain basic life processes, including: respiration, heartbeat, renal function, brain and nerve function, blood circulation, active transport, and synthesis of proteins and other complex molecules 2. Predictive equations for RMR – calculations based on body weight, height, age, and gender to estimate RMR needs 3. Equations possible: Harris-Benedict equations, Mifflin-St. Jeor equations, and Weight-Only equations C. Energy Expenditure of Physical Activity 1. Muscle requires more energy depending on the tasks. Physical activity accounts for about 15–30% of total energy expenditure 2. Figures and Tables a. Table 8.2 – physical activity level categories and walking equivalence b. Table 8.3 – energy expended on various activities D. Thermic Effect of Food 1. The thermic effect of food represents the metabolic response to food and the increase in energy expenditure associated with the body’s processing of food E. Thermoregulation 1. Refers to the adjustments in metabolism necessary to maintain the body’s core temperature of about 98.2–98.6°F © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Key Terms a. Heat stress – metabolic response to heat exposure, resulting in heat rash, heat cramps, heat exhaustion, and heat stroke IV. Body Weight: What Should We Weigh? A. Ideal Body Weight Formulas 1. These evolved directly from height-weight tables and are intended to provide guidance to health practitioners when determining overall mortality risk in a given population B. Body Mass Index 1. Is an indication of body adiposity but doesn’t directly measure body fat. Calculated from body mass index equaling weight over height squared 2. Figures and Tables a. Table 8.4 – ideal body weight formulas b. Figure 8.4 – BMI values used to categorize weight c. Figure 8.5 – example of growth curves d. Figure 8.6 – obesity prevalence in the United States e. Table 8.5 – disease risk relative to normal BMI and waist circumference V. Measuring Body Composition A. Field Methods 1. Skinfold thickness – skinfold measurements are used as an indicator of body fat based on the assumption that the thickness of the subcutaneous fat directly correlates with total body fat 2. Bioelectrical impedance – this field technique assesses the twocompartment model, based on the principle that the flow of electricity is facilitated in fat-free tissue high in water and electrolyte content, but is impeded by fat tissue low in water and electrolytes 3. Figures and Tables a. Figure 8.7 – measuring triceps skinfold with a Lange caliper to estimate body fat b. Figure 8.8 – hand-held device used to measure bioelectrical impedance B. Laboratory Methods 1. Densitometry: underwater weighing – density of fat is about 0.9 g/mL, and density of fat-free mass is about 1.1 g/mL. Body fat percentage may be calculated if whole-body density is known. The body is submerged in water and the volume of water displaced is used to calculate the body composition 2. Densitometry: air displacement – use of air to measure change in pressure caused by volume occupied by the person in the chamber being used to measure displacement 3. Dual-energy X-ray absorptiometry – involves scanning subjects with X-rays at two different energy levels

4. Other imaging techniques – computed tomography and magnetic resonance imaging may both be used to measure body composition, but both are very expensive 5. Figures and Tables a. Figure 8.9 – apparatus for underwater weighing to determine body density b. Figure 8.10 – air displacement plethysmography determines body density by measuring the amount of air displaced c. Figure 8.11 – duel-energy X-ray absorptiometry uses two X-ray beams of different energy to determine fat-free mass, fat mass, and bone tissue density VI. Regulation of Energy Balance and Body Weight A. Hormonal Influences 1. Hunger and satiety control meal-to-meal eating behavior, and both are under the influence of hormones 2. Key Terms a. Arcuate nucleus – the subcortical region of the brain that secretes appetite-enhancing neuropeptide Y and appetite-suppressing melanocortins b. Orexigenic – pertaining to increasing or stimulating the appetite c. Anorexigenic – capable of producing anorexia or diminishing appetite d. Leptin resistance – concept that, despite increased circulating leptin levels and adequate leptin receptors, the feeling of hunger persists and food intake does not diminish 3. Leptin – hormone secreted by white adipose tissue that interacts with the hypothalamus to reduce hunger 4. Insulin – suppresses hunger through its action on orexigenic and anorexigenic neurons; effects are less robust than leptin 5. Ghrelin – produced predominantly in the stomach and stimulates the feeling of hunger 6. Other anorexigenic hormones a. Cholecystokinin is produced in the small intestine in response to food intake. It binds to receptors in the hypothalamus and downregulates mRNA expression b. Pancreatic polypeptide – synthesized in the pancreas, secreted in response to food intake, and the mechanism of action is not certain c. Glucagon – like peptide, it occurs in the intestine in proportion to caloric intake; release is delayed in obese individuals; reduces gastric emptying and intestinal motility d. Peptide YY – produced in the small and large intestines; counters the effects of CCK by inhibiting intestinal motility and secretion of digestive juices 7. Figures and Tables B. Table 8.6 – agents of energy regulation, intestinal microbiota © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

1. Found throughout the gastrointestinal tract and participate in nutrient digestion and utilization C. Environmental Chemicals 1. Exposure to certain chemicals may play a role in body fat accumulation 2. Key Terms a. Obesogens – endocrine-disrupting chemicals in the environment, including the diet, that alter lipid metabolism by binding to hormone receptors D. Lifestyle Influences 1. Diet and physical activity are the most obvious factors that influence energy balance and body weight VII. Health Implications of Altered Body Weight A. Metabolic Syndrome 1. Group of risk factors associated with increased risk of cardiovascular disease, including: central obesity, increased fasting plasma glucose, decreased plasma HDL cholesterol, and hypertension 2. Key Terms a. Metabolic syndrome – clustering of risk factors for cardiovascular disease and type 2 diabetes, including elevated blood pressure and obesity 3. Figures and Tables a. Table 8.7 – criteria for clinical diagnosis of metabolic syndrome B. Insulin Resistance 1. Generally defined as the inability of target tissues to respond to insulin, causing elevated blood glucose C. Weight Loss Methods 1. Methods could be caloric restriction, increased exercise. Overall requirement to losing body fat requires a negative energy balance over an extended period of time VIII.

Summary 1. Individuals should try to maintain a health energy balance, consuming the amount of energy equal to the amount of energy expenditure in the body 2. Total energy expenditure includes basal metabolic rate, physical activity, and the thermic effect of food 3. Consuming more than needed puts a person at positive energy balance, resulting in body fat accumulation that increases the chances of disease and mortality

Resources Additional Resource •

Ma, C.M., Yin, F.Z., Liu, X.L., Wang, R., Lou, D.H., & Lu, Q. (2016). How to simplify the diagnostic criteria of metabolic syndrome in adolescents. Pediatric Neonatology, S1875-9572. Article ID. How to simplify the diagnostic criteria of metabolic syndrome in adolescents

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. • What are the health risk differences between having an underweight BMI percentage compared to an overweight BMI percentage? • Underweight could lead to malnutrition, or the body missing out on vital nutrients. This could affect development, growth, and mental development. • Overweight could lead to cardiovascular disease and put the individual at risks for insulin resistance, glucose intolerance, increased triglycerides, and increased blood pressure. • Discuss the methods to test BMI. • Skinfold thickness, bioelectrical impedance, densitometry: underwater weighing, densitometry: air displacement, dual-energy X-ray absorptiometry, CT scans, and MRI scans.

Assignment – Individual Paper •

Many hormones aid in energy regulation; however, some may lead to obesity when they are not balanced or obesity may lead to an imbalance in them. Make a table of the eight agents and within the table discuss their role in obesity and how they affect hunger and appetite.

Answer Keys Worksheet 1: Responding to Research – Metabolic Syndrome in Adolescents 1. a 2. c 3. only in Han adolescents 4. Visceral fat causes an increased risk of cardiovascular disease by affecting metabolism and increasing fatty acid release. Worksheet 2: Nutrition Lab – Body Mass Index and Effects 1. 104.5 kg/1.832 m = 31.2% 2. Gary is considered obese with this high of a BMI. A healthy BMI percentage range is between 18.5% and 25%. 3. Gary’s BMI category is obese, class I. 4. Gary needs to adapt a healthier diet and increase his physical activity.

Worksheet 1: Research Study – Metabolic Syndrome in Adolescents Metabolic syndrome is an increasingly growing risk to the population, especially the obese population. The syndrome involves glucose intolerance, hypertension, increased triglycerides, obesity risks, and insulin resistance. It is becoming more prevalent among adolescents due to lack of physical activity and eating behaviors. Read the following article and then respond to the questions. • Ma, C.M., Yin, F.Z., Liu, X.L., Wang, R., Lou, D.H., & Lu, Q. (2016). How to simplify the diagnostic criteria of metabolic syndrome in adolescents. Pediatric Neonatology, S1875-9572. Article ID How to simplify the diagnostic criteria of metabolic syndrome in adolescents 1. Using the height-corrected definition to identify metabolic syndrome is accurate enough to identify the syndrome in adolescents. a. True b. False __________ 2. Rachel is concerned that her son has metabolic syndrome. She wants to get Lance tested to make sure he is healthy. What are the screening results that identify metabolic syndrome? a. HDL > 1.05, blood pressure < 130/85 mmHg, triglycerides < 1.7 b. central obesity WHtR > 0.46 c. triglycerides >1.75, central obesity >90th percentile, HDL-C < 1.0 d. fasting blood glucose > 5.1 mmol/L __________ 3. Height-corrected metabolic syndrome identification can be used in adolescents __________. a. 13–17 years of age b. of all ages c. belonging only to Han __________ 4. How does the increase of visceral fat affect health?

Worksheet 2: Nutrition Lab – Body Mass Index and Effects Gary is a 38-year-old male, wondering what his body mass index is. Gary weighs 230 pounds and is 6 foot even. Answer the questions below. 1. What is Gary’s calculated body mass index?

2. Is this considered high for a male his size and age? What should his body mass index be to remain within a healthy range?

3. Based on Gary’s BMI results, which BMI category describes his BMI?

4. What do you recommend for Gary if he wants to change his BMI?

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 9 – Water-Soluble Vitamins Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Responding to Research – Thiamin Impact Worksheet 2: Labeling It – Functional Roles of Water-Soluble Vitamins

Chapter Outline I. Introduction 1. Historical events led to the discovery of vitamins, usually due to an outbreak from a deficiency in the vitamin. Vitamins are organic compounds with regulatory functions. They are required 2. Key Terms a. Beriberi – a condition resulting from a thiamin deficiency b. Recommended dietary allowances – the average daily dietary intake level of a nutrient that is thought to be sufficient to meet the nutrient requirements of about 97% of healthy individuals c. Adequate intakes – a recommended daily dietary nutrient intake based on the nutrient intake levels of healthy people; an AI is thought to exceed the daily requirement for a given nutrient d. Estimated average requirements – the amount of a nutrient thought to meet the requirements of 50% of healthy individuals in a specified age and gender group 3. Figures and Tables a. Table 9.1 – water-soluble vitamins b. Table 9.2 – some common signs associated with water-soluble vitamin deficiencies c. Figure 9.1 – the vitamins, including some functional roles of the watersoluble vitamins II. Vitamin C (Ascorbic Acid) 1. Isolated in 1928, and structure determined in 1933. Vitamin deficiency leads to scurvy. L-isomer is the biologically active vitamin in humans 2. Key Terms a. Scurvy – a condition resulting from vitamin C deficiency © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. Figures and Tables a. Figure 9.2 – structures and interconversion of ascorbic acid and dehydroascorbic acid b. Figure 9.3 – synthesis of ascorbic acid c. Table 9.4 – vitamin C content of selected foods A. Sources 1. Primary sources include fruits and vegetables B. Digestion, Absorption, Transport, and Storage 1. Vitamin C doesn’t require digestion prior to being absorbed into intestinal cells. Absorption of ascorbic acid across the intestinal cell brush border membrane occurs throughout the small intestine, especially proximal jejunum, and requires sodium-dependent vitamin C transporters (SVCT) 1 and 2. Ascorbic acid is absorbed by glucose transporters GLUT 1 and 3; following absorption, dehydroascorbic acid is rapidly reduced to ascorbic acid by dehydroascorbic acid reductase in the intestinal cell C. Functions and Mechanisms of Action 1. Vitamin C functions as an antioxidant and a cosubstrate for enzyme activity 2. Key Terms a. Xenobiotics – foreign chemicals such as drugs, carcinogens, pesticides, food additives, pollutants, or other noxious compounds b. Free radicals – an atom or molecule that has one or more unpaired electrons c. Hydroxyl radical – an oxygen-centered radical that can be generated in the body when it is exposed to γ rays, low-wavelength electromagnetic radiation d. Hydroperoxyl radical – a protonated superoxide radical e. Superoxide radical – an oxygen-centered free radical f. Alkoxyl radical – a monovalent radical consisting of an alkyl group united with oxygen. Alkyl groups are derived from alkanes by the removal of one hydrogen atom and have the general formula CnH2n+1 g. Peroxyl radical – a radical that contains a peroxyl group h. Singlet oxygen – an electronically excited radical in which one of oxygen’s electrons is excited to an orbital above the one it normally occupies i. Prophylactic – a substance or regime that helps to prevent disease or illness j. Epidemiological studies – the science concerned with studying those factors that influence the frequency and distribution of disease in a defined human population 3. Figures and Tables a. Figure 9.4 – ascorbate functions in the hydroxylation of peptide-bound proline and lysine in the synthesis of collagen b. Figure 9.5 – amidation of peptides with C-terminal glycine requires vitamin C D. Interactions with Other Nutrients © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

1. Interacts with iron E. Metabolism and Excretion 1. Vitamin C in excess of tissue needs and storage capacity is excreted intact or catabolized prior to urinary excretion 2. Figures and Tables a. Figure 9.6 – vitamin C and the formation of its metabolites excreted in the urine F. Recommended Dietary Allowance 1. For adult men, it is 75 mg and for adult women, it is 60 mg. During pregnancy and lactation, recommendations for vitamin C increase to 100 mg and 120 mg, respectively G. Deficiency: Scurvy 1. Scurvy is typically manifested when the total body vitamin C pool falls below about 300 mg and plasma vitamin C concentrations drop to less than about 0.2 mg/dL 2. Key Terms a. Petechiae – skin discolorations caused by ruptured small blood vessels b. Hypochondriasis – abnormal anxiety about one’s own health H. Toxicity 1. Daily intakes up to 2 g of vitamin C are routinely consumed without adverse effects. Most common side effect is gastrointestinal problems characterized by abdominal pain and osmotic diarrhea 2. Key Terms a. Hemochromatosis – an inherited disorder characterized by excessive iron absorption and iron overload in the body b. Thalassemia – a hereditary form of anemia associated with defective synthesis of hemoglobin c. Sideroblastic anemia – an inherited disorder that affects red blood cell production and function I. Assessment of Nutriture 1. Plasma vitamin C concentrations respond to changes in dietary vitamin C intake III. Thiamin (Vitamin B1) 1. Isolated in 1912 and structure determined in mid-1930s 2. Figures and Tables a. Figure 9.7 – structure of thiamin A. Sources 1. Meats are the major source 2. Figures and Tables a. Table 9.5 – thiamin content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Thiamin exists in a few forms in plant foods. In animal products, about 95% of thiamin is phosphorylated as primary TDP and about 5% exists as thiamin monophosphate and thiamin triphosphate. Absorption of free thiamin occurs via diffusion throughout the small intestine and by © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

transporter found mainly in the duodenum and jejunum. Thiamin is released from intestinal cells into the blood typically within 1–2 hours for distribution to tissues C. Functions and Mechanisms of Action 1. Thiamin is involved in essential coenzyme and noncoenzyme roles including: energy production and nutrient metabolism and nervous system functions 2. Figures and Tables a. Figure 9.8 – various vitamin cofactors and their action sites in energy metabolism b. Figure 9.9 – oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex c. Figure 9.10 – first steps in the decarboxylation of pyruvate by thiamin diphosphate D. Metabolism and Excretion 1. Thiamin, TMP, and TDP in excess of tissue needs and storage capacity are excreted intact or catabolized prior to urinary excretion E. Recommended Dietary Allowance 1. For adult men, it is 1.2 mg/day and for adult women, it is 1.1 mg/day. Thiamin recommendations with pregnancy and lactation increase to 1.4 mg/day and 1.5 mg/day, respectively F. Deficiency: Beriberi 1. Deficiency impacts energy production as well as other body processes secondary to reductions in the production of various intermediates normally generated during nutrient metabolism 2. Key Terms a. Ophthalmoplegia – paralysis of the ocular muscles b. Nystagmus – constant, involuntary movement of the eyeball G. Toxicity 1. No Tolerable Upper Intake Level has been established and no side effects have been reported from oral intakes up to about 500 mg daily H. Assessment of the Nutriture 1. Thiamin status can be assessed by measuring thiamin and/or TDP in the blood or urine and by measuring erythrocyte transketolase activity in hemolyzed whole blood IV. Riboflavin (Vitamin B2) 1. Discovered in 1917 and the structure determined in 1933 2. Figures and Tables a. Figure 9.11 – structures of riboflavin and its coenzyme forms A. Sources 1. Riboflavin is found in foods of animal origin 2. Figures and Tables a. Table 9.6 – riboflavin content of selected foods B. Digestion, Absorption, Transport, and Storage

1. Riboflavin found in foods attached noncovalently to proteins must be released from the protein prior to absorption. This process is accomplished by the actions of hydrochloric acids secreted within the stomach and proteases secreted by the stomach, pancreas, and small intestine. FAD pyrophosphatase converts FAD to FMN. FMN in turn is converted to free riboflavin by FMN phosphatase. Free riboflavin is absorbed across the intestinal brush border membrane by an energy-dependent riboflavin vitamin transport 3. Another riboflavin transporter, RFVT1, carries riboflavin across the basolateral membrane of intestinal cells C. Functions and Mechanisms of Action 1. FMN and FAD function as coenzymes for a variety of oxidative enzymes and remain bound to the enzymes during the oxidation-reduction reactions. Flavoprotein have roles in nutrient metabolism and energy production and riboflavin has selected pharmacological uses 2. Figures and Tables a. Figure 9.12 – oxidation and reduction of isoalloxazine ring D. Metabolism and Excretion 1. Riboflavin and its metabolites are excreted primarily in the urine. The amount excreted is typically at least 120 µg/day or 80 µg/g creatinine E. Recommended Dietary Allowance 1. Riboflavin for adult men is 1.3 mg/day and for adult women is 1.1 mg/day. Pregnancy and lactation increase the recommended daily intake to 1.4 mg/day and 1.6 mg/day, respectively F. Deficiency: Ariboflavinosis 1. Deficiency of riboflavin rarely occurs in isolation and is usually accompanied by other nutrient deficiencies. Some clinical signs after 3–4 months of inadequate intake include painful lesions or vertical fissures on the outside of the lips, inflammation of the tongue, and red or bloody swollen oral cavity G. Toxicity 1. No Tolerable Upper Intake Level has been established and doses of up to 400 mg have been consumed in those with migraines without side effects H. Assessment of Nutriture 1. Glutathione reductase activity measurement, FMN-dependent enzyme activity measurement, pyridoxamine phosphate oxidase measurement, and vitamin B6 coenzyme forms may all be used as biomarkers of riboflavin status. Urinary riboflavin excretion is also used to assess status V. Niacin (Vitamin B3) 1. Discovered through the condition pellagra. Isolated in 1937 2. Key Terms a. Pellagra – a condition that results from niacin deficiency 3. Figures and Tables a. Figure 9.13 – structures of nicotinic acid and nicotinamide A. Sources 1. Found in several food groups, with the best being fish and meats © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Figures and Tables a. Table 9.7 – niacin content of selected foods b. Figure 9.14 – structures of NAD and NADP c. Figure 9.15 – NAD+ and NADP+ synthesis from the amino acid tryptophan B. Digestion, Absorption, Transport, and Storage 1. Digestion of NAD and NADP is needed for niacin’s absorption. A pyrophosphatase is required for phosphate hydrolysis from NADP. NADP is then hydrolyzed by glycohydrolase to release free nicotinamide. Nicotinamide and nicotinic acid are absorbed primarily in the small intestine by sodium-dependent, carrier-mediated diffusion. Within the colon, nicotinic acid absorption occurs by a sodium-independent, highaffinity carrier C. Functions and Mechanisms of Action 1. Over 200 enzymes, primarily dehydrogenases, require the coenzymes NAD and NADP 2. Figures and Tables a. Figure 9.16 – oxidation and reduction of the nicotinamide moiety; the role of NAD is dehydrogenation reactions D. Metabolism and Excretion 1. NAD and NADP undergo degradation in cells by glycohydrolase to form ADP-ribose and nicotinamide. The released nicotinamide is then methylated and oxidized in the liver into a variety of products that are excreted in the urine E. Recommended Dietary Allowance 1. Niacin for adult men is 16 mg of niacin equivalents and for adult women it is 14 mg of niacin equivalents per day. In pregnancy and lactation, it increases to 18 mg and 17 mg of niacin equivalents, respectively F. Deficiency: Pellagra 1. The four main signs are dermatitis, dementia, diarrhea, and death G. Toxicity 1. The Tolerable Upper Limit Level for adults for niacin from supplements and from fortified foods has been set at 35 mg/day H. Assessment of Nutriture 1. Most methods involve measurement of one or more urinary metabolites of the vitamin VI. Pantothenic Acid 1. Discovered in 1954, although it was isolated in about 1931 with its structure determined in 1939 A. Sources 1. Found widely distributed in foods 2. Figures and Tables a. Table 9.8 – pantothenic acid content of selected foods b. Figure 9.17 – synthesis of coenzyme A from pantothenic acid B. Digestion, Absorption, Transport, and Storage

1. About 85% of the pantothenic acid in food is bound as a component of coenzyme A. During digestion in the small intestine, CoA is hydrolyzed by pyrophosphatase to 4′-phosphopantetheine, which is then dephosphorylated by phosphatase to pantetheine, which is converted to pantothenic acid by pantotheinase. Absorption occurs principally in the jejunum by passive diffusion. Pantothenic acid from the intestinal cells enter the portal blood for transport to the liver and other tissues 2. Figures and Tables a. Figure 9.18 – structures of coenzyme A C. Functions and Mechanisms of Action 1. Pantothenic acid is needed by cells for the synthesis of CoA and the 4′phosphopantetheine moiety; upon donation from CoA, is required for the activity of the acyl carrier protein, a component of the fatty acid synthase complex D. Metabolism and Excretion 1. Pantothenic acid is excreted intact primarily in the urine E. Adequate Intake 1. Pantothenic acid recommended daily intake is 5 mg for adults, and 6 mg/day during pregnancy and 7 mg/day during lactation F. Deficiency: Burning Foot Syndrome 1. Syndrome is characterized by a sensation of burning in the feet and neuritis. Usually in conjunction with multiple nutrient deficiencies G. Toxicity 1. Intakes of about 10 g of pantothenic acid as calcium pantothenate daily for up to 6 weeks have not caused problems; however, higher intakes of 15–20 g have been associated with mild intestinal distress H. Assessment of Nutriture 1. Urinary pantothenic acid excretion is considered to be a better indicator compared to blood VII. Biotin 1. Discovered in 1931 and the structure was discovered in 1941 2. Figures and Tables a. Figure 9.19 – structure of biotin A. Sources 1. Biotin is found widely distributed in foods B. Digestion, Absorption, Transport, and Storage 1. Protein – bound biotin requires digestion by enzymes prior to absorption. Proteolysis by pepsin and intestinal proteases yields free biotin and/or biocytin. Biotin absorption occurs by both passive diffusion and carriermediated transport. Transport of biotin across the basolateral membrane of the enterocyte for entrance into the blood is carrier mediated 2. Figures and Tables a. Figure 9.20 – structure of biocytin C. Functions and Mechanisms of Action

1. Biotin functions in cells as a coenzyme carrier for the transfer of activated bicarbonate to substrates. Biotin functions in a noncoenzyme capacity in regulating gene expressions 2. Key Terms a. Carboxylation – the addition of a carboxyl group to a molecule 3. Figures and Tables a. Figure 9.21 – biotin bound to the lysine residue of carboxylase and functioning as a carrier of activated CO2 b. Table 9.9 – biotin-dependent enzymes c. Figure 9.24 – role of biotin in the oxidation of propionyl-CoA d. Figure 9.25 – role of biotin in leucine catabolism D. Metabolism and excretion 1. Catabolism of the biotin holocarboxylases by proteases ultimately yields biocytin 2. Biocytin is then degraded by biotinidase to lysine and free biotin 3. Biotin is mainly excreted in the urine with some having been synthesized by intestinal bacteria 4. Figures and Tables a. Figure 9.26 – selected metabolites from biotin degradation E. Adequate Intake 1. Biotin recommendations for adults in 30 µg per day and increases to 3 µg per day during lactation F. Deficiency 1. Deficiency has resulted from excessive consumption of raw egg whites, although rare. Some neurological symptoms associated with biotin deficiency include lethargy, paresthesia in extremities, hypotonia, depression, and hallucinations G. Toxicity 1. Toxicity from oral biotin has not been reported and no Tolerable Upper Intake Level has been established H. Assessment of Nutriture 1. Biotin evaluation may be done through the blood and urine VIII. Folate 1. Folate was discovered in 1941 and its chemical synthesis in a lab was reported in 1945 2. Figures and Tables a. Figure 9.27 – structures of folic acid, folate, and tetrahydrofolate and its derivatives A. Sources 1. Folate is found in significant quantities in vegetables; raw foods are usually higher in folate than cooked 2. Figures and Tables a. Table 9.10 – folate content of selected foods B. Digestion, Absorption, Transport, and Storage

1. Folic acid in fortified foods and supplements does not need to undergo digestion. Folate in foods is found in polyglutamate forms and needs to be digested to monoglutamate forms in order to be absorbed. The main carrier for transporting folate into intestinal cells is the proton-coupled folate transporter. Folic acid may be absorbed when present in high concentrations in a more acidic environment by passive diffusion. Uptake of folate into the liver and other tissues is carrier mediated and most folate is stored in the liver C. Functions and Mechanisms of Action 1. THF derivatives are found in the mitochondria, cytosol, and nucleus, and serve as donors of single- or one-carbon groups in a variety of reactions. These reactions involve metabolism of several nutrients including choline and some amino acids, production of purines and pyrimidines, and DNA synthesis and repair 2. Figures and Tables a. Figure 9.28 – interconversions of coenzyme forms of tetrahydrofolate b. Table 9.11 – forms of folate and their metabolic roles in the body c. Figure 9.29 – role of folate in histidine catabolism d. Figure 9.30 – resynthesis of methionine from homocysteine, showing roles of folate and vitamin B12 D. Interactions with Other Nutrients 1. Folate has a synergistic relationship with vitamin B12 E. Metabolism and Excretion 1. Folate is excreted in both the urine and the feces F. Recommended Dietary Allowance 1. Folate recommendation for adults is 400 µg per day of dietary folate equivalents; this increases to 600 µg per day during pregnancy and 500 µg per day during lactation G. Deficiency: Megaloblastic Macrocytic Anemia 1. Folate deficiency causes a release of red blood cells into circulation that are fewer than normal in number as well as large and immature, resulting in megaloblastic macrocytic anemia 2. Figures and Tables a. Figure 9.31 – genesis and maturation of the red blood cells; red blood cells characteristic of microcytic and megaloblastic anemia H. Toxicity 1. A Tolerable Upper Intake Level for adults of 1,000 µg for synthetic folic acid in supplements or from fortified foods. Side effects have been documented with folate intakes of 15 mg I. Assessment of Nutriture 1. Folate is often assessed by measuring folate concentrations in the plasma, serum, or red blood cells IX. Vitamin B12 (Cobalamin) 1. Isolated in 1948 2. Figures and Tables © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

a. Figure 9.32 – structure of vitamin B12 A. Sources 1. Vitamin B12 sources are primarily from animal products 2. Figures and Tables a. Table 9.12 – vitamin B12 content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Ingested cobalamins must first be released from the food proteins to which they are bound. Pepsin and hydrochloric acid in the stomach digest proteins. Vitamin B12 ingested through foods, supplements, and fortified foods is not bound to proteins and doesn’t require initial hydrolysis. In the stomach, the now free vitamin B12 binds to an R protein that moves it from the stomach to the duodenum. From the duodenum, the B12-IF complex travels to the distal ileum and interacts with cubam complex receptor on the brush border membrane of ileal cells. B12 is carried across the ileum’s basolateral membrane and binds to transcobalamin II for transport in portal blood. Following absorption, B12 appears in the blood in about 3–4 hours. Unlike other water-soluble vitamins, B12 can be stored in the body for relatively long periods 2. Key Terms a. Chaperones – soluble intracellular proteins that bind to and deliver minerals to specific intracellular locations 3. Figures and Tables a. Figure 9.33 – vitamin B12 absorption C. Functions and Mechanisms of Action 1. Two enzymatic reactions require vitamin B12, both facilitating nutrient metabolism and energy production, and indirectly the synthesis of purines and pyrimidines for use in nucleic acids 2. Figures and Tables a. Figure 9.34 – role of vitamin B12 in oxidation of L-methymalonyl-CoA D. Metabolism and Excretion 1. Vitamin B12 undergoes little to no degradation prior to excretion E. Recommended Dietary Allowance 1. Vitamin B12 recommended for adults is 2.4 µg per day; increase of 0.2 µg per day for pregnancy and 0.4 µg per day for lactation F. Deficiency: Megaloblastic Macrocytic Anemia 1. Similar to folate, vitamin B12 deficiency causes DNA synthesis to become deranged, along with cell differentiation and maturation 2. Key Terms a. Achlorhydria – lack of hydrochloric acid in gastric juices G. Toxicity 1. No clear toxicity has been reported; no Tolerable Upper Intake Level established H. Assessment of Nutriture 1. Vitamin B12 status may be assessed using serum levels of cobalamin, methylmalonic acid, or using deoxyuridine suppression test © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

X. Vitamin B6 1. Vitamin B6 was isolated in 1934 and its structure confirmed in 1939 2. Figures and Tables a. Figure 9.35 – vitamin B6 structures A. Sources 1. All B6 vitamers are found in food; main sources are animal products 2. Figures and Tables a. Table 9.13 – vitamin B6 content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Prior to absorption of vitamin B6, the phosphorylated vitamers must be dephosphorylated. Alkaline phosphatase hydrolyzes the phosphate from the phosphorylated vitamers to yield free pyridoxine, pyridoxal, or pyridoxamine. These are absorbed in the jejunum by passive diffusion. Most can be released directly into portal blood, and the liver is the main organ that takes up and metabolizes newly absorbed vitamin B6 2. Figures and Tables a. Figure 9.36 – vitamin B6 metabolism in the liver C. Functions and Mechanisms of Action 1. The pyridoxal phosphate form of vitamin B6 functions as a coenzyme for over 100 enzymes, majority being involved in nutrient metabolism and also affect the production of neurotransmitters, nucleic acids, heme, sphingolipids, carnitine, and glucose 2. Figures and Tables a. Figure 9.37 – covalent bonds of an acid that can be made labile by its binding to PLP-containing enzymes b. Figure 9.38 – role of vitamin B6 in transamination, phase 1 and phase 2 D. Metabolism and Excretion 1. Vitamin B6 is mainly excreted in the urine, with little in the feces E. Recommended Dietary Allowance 1. Vitamin B6 is recommended in amount of 1.3 mg per day for adult men between the ages of 19 and 50 years; for men older than 51, it is 1.7 mg per day. For adult women between the ages of 19 and 50 years, it is 1.3 mg per day, and over 51 years is 1.5 mg per day. Pregnancy and lactation recommendations are 1.9 mg per day and 2.0 mg per day, respectively F. Deficiency 1. Vitamin B6 deficiency is rare in the United States. Signs and symptoms include rash on the face, neck, shoulders, and buttocks areas, weakness, fatigue, cheilosis, glossitis, angular stomatitis, and neurological problems 2. Key Terms a. Seborrheic dermatitis – an inflammatory skin condition G. Toxicity 1. Intakes in excess of 2 g per day of pyridoxine are usually associated with paresthesia in the feet and hands, and impaired motor control or ataxia. High intakes may cause degeneration of neurons. The Tolerable Upper Intake Level for vitamin B6 is 100 mg per day for adults © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

H. Assessment of Nutriture 1. Plasma measurements of pyridoxal phosphate are the best indicators of vitamin B6 levels XI. Summary 1. Water-soluble vitamins are vitamin C and the B complex; many of these vitamins are stored within the liver and cells, while much of the excess is excreted through the urine and feces

Resources Suggested Readings • Lanska DJ. Historical aspects of the major neurological vitamin deficiency disorders: the water soluble vitamins. Handbook of Clinical Neurology. 2010; 95:445–76. • McCollum EV. A History of Nutrition. Boston: Houghton Mifflin. 1957 • Baron JH. Sailors’ scurvy before and after James Lind: a reassessment. Nutr Rev. 2009; 67:315–32. • De Luca LM, Norum KR. Scurvy and cloudberries: a chapter in the history of nutritional sciences. J Nutr. 2011; 141:2101–05. • Carr AC, Vissers MCM. Synthetic or food-derived vitamin C—are they equally bioavailable? Nutrients. 2013; 5:4284–4304. • NIH. Office of Dietary Supplements. Vitamin C. https://ods.od.nih.gov/ factsheets/VitaminC-HealthProfessional/ • Bettendorff L, Wins P. Thiamin diphosphate in biological chemistry: new aspects of thiamin metabolism, especially triphosphate derivatives acting other than as cofactors. FEBS Journal. 2009; 276:2917–25. • Symposium: advances in the understanding of the biological role of biotin at the clinical, biochemical, and molecular level. J Nutr. 2009; 139:152–70. • Friso S, Choi S-W. Gene-nutrient interactions and DNA methylation. J Nutr. 2002; 132:S2382–87. • Green R. Ins and outs of cellular cobalamin transport. Blood. 2010; 115:1476–77. • Jacobsen DW, Glushchenko AV. The transcobalamin receptor redux. Blood. 2009; 113:3–4. • Stover PJ. Vitamin B12 and older adults. Current Opin Clin Nutr Metab Care. 2010; 13:24–27. • Hellmann H, Mooney S. Vitamin B6: a molecule for human health? Molecules. 2010; 15:442–59. • Mooney S, Leuendorf J, Hendrickson C, Hellmann H. Vitamin B6: a long known compound of surprising complexity. Molecules. 2009; 14:329–51. Additional Resource •

Costin, B. N. & Miles, M. F. (2014). Molecular and neurologic responses to chronic alcohol use. Handbook of Clinical Neurology, 125, 157–171. Article ID Molecular and neurologic responses to chronic alcohol use

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

What are the main coenzymes for each of the water-soluble vitamins and which processes would be affected if the body was low in that vitamin?

•

Discuss the storage sites of each water-soluble vitamin. • Vitamin C – adrenal and pituitary glands, eyes, brain, white blood cells • Vitamin thiamin – muscle, heart, brain, kidneys, liver • Vitamin riboflavin – liver, kidneys, heart • Vitamin niacin – liver • Vitamin pantothenic acid – liver, adrenal glands, kidneys, brain, heart • Vitamin biotin – liver, muscle, brain • Vitamin folate – liver • Vitamin B12 – liver, muscle, pituitary gland, bone, kidneys, heart, brain, spleen

•

Vitamin B6 – muscle, liver, brain, kidneys, spleen

Assignment – Individual Paper •

The Tricyclic Acid involves a few of the water-soluble vitamins within the process. Using either a figure or a diagram, explain the roles of the water-soluble vitamins within the TCA.

Answer Keys Worksheet 1: Responding to Research – Metabolic Syndrome in Adolescents 1. a 2. d 3. a month, indefinitely 4. Thiamin isn’t being absorbed due to nutrient competition in the intestines. Therefore, thiamin must be administered prior to other nutrients being administered, so the thiamin is absorbed. Worksheet 2: Labeling It – Functional Roles of Water-Soluble Vitamins 1. folate; vitamin B12 2. thiamin; riboflavin; niacin; folate; biotin; pantothenic acid; vitamin B6; vitamin B12 3. biotin; pantothenic acid; folate; vitamin B6 4. hematopoietic; energy production and nutrient metabolism; gene expression 5. antioxidant; enzyme cosubstrate

Worksheet 1: Research Study – Thiamin Impact Thiamin is a water-soluble vitamin, known as vitamin B1. The lack of thiamin results in deficiencies that attack the nervous system. One cause of thiamin deficiency is alcoholism. It is vital to know the signs and symptoms of thiamin deficiency in alcoholism because the way it is treated could save or ruin a life. Read the following article and then respond to the questions. • Costin, B. N. & Miles, M. F. (2014). Molecular and neurologic responses to chronic alcohol use. Handbook of Clinical Neurology, 125, 157–171. Article ID Molecular and neurologic responses to chronic alcohol use 1. Alcoholism causes thiamin deficiency, which could lead to Wernicke’s encephalopathy. a. True b. False __________ 2. Steve has recently been drinking a lot. He is enjoying his social life, almost nightly, and there are many nights when Steve will black out after drinking. Tonight, Steve is acting very strange. He can’t tell you what he ate today or what he did today, he isn’t able to do simple math, his eyes cannot focus, and he is walking with a limp as though he is injured but he isn’t. What is happening or needs to be done? a. Steve is just drunk and needs to sleep it off. b. Steve needs to drink some water because his symptoms are due to dehydration. c. Steve needs to have an MRI done of his brain to see if he is suffering from Wernicke’s encephalopathy. d. Steve needs immediate administration of thiamin because he is at risk for Wernicke’s encephalopathy. __________ 3. Following the diagnosis of Wernicke’s encephalopathy, the patient must take thiamine a minimum of __________, if not __________. a. a month; indefinitely b. several days; a month c. 1 week; indefinitely __________ 4. What is the risk and treatment of Wernicke’s encephalopathy in alcoholics?

Worksheet 2: Labeling It – Functional Roles of Water-Soluble Vitamins Complete the figure by adding the water-soluble vitamins to the functional roles listed.

1. Which water-soluble vitamins have a functional role in the hematopoietic process?

2. Which water-soluble vitamins have a functional role in energy production and nutrient metabolism?

3. Which water-soluble vitamins that have a functional role in gene expression?

4. What are the functions of the B-complex vitamins?

5. What are the functions of Vitamin C?

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 10 – Fat-Soluble Vitamins Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Fat-Soluble Vitamins and Cardiovascular Effects Worksheet 2: Nutrition Lab – Fat-Soluble Meal Plan

Chapter Outline I. Introduction 1. This chapter covers the fat-soluble vitamins A, D, E, and K, as well as the carotenoids; and the sources, digestion and absorption, transport, metabolism, and storage, functions and mechanisms of actions, interactions with other nutrients, metabolism and excretion, recommended dietary allowance, deficiencies, toxicities, and assessment of each nutriture 2. Figures and Tables a. Table 10.1 – the fat-soluble vitamins: function, food sources, and recommended dietary allowance or adequate intake b. Table 10.2 – some common signs associated with fat-soluble vitamin deficiencies II. Vitamin A and Carotenoids 1. Vitamin A was discovered in 1915, with the term vitamin A generally referring to a group of compounds that possess the biological activity of alltrans retinol 2. Key Terms a. Isoprenoid – refers to the structure of the side chains of five-carbon units, as found in vitamins E and K A. Sources 1. Both preformed vitamin A (retinoids) and carotenoids are found naturally in foods 2. Vitamin is found primarily in selected foods of animal origin; carotenoids are synthesized by a wide variety of plants 3. Figures and Tables © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

a. Table 10.3 – vitamin A and β-carotene contents of selected foods b. Figure 10.1 – vitamin A and carotenoid structures B. Digestion and Absorption 1. Vitamin A requires some digestion before absorption in the small intestine 2. Carotenoids and retinyl esters are initially hydrolyzed from protein by pepsin in the stomach to form fat globules; these are then emptied into the duodenum where bile emulsifies them 3. Any remaining retinyl esters or carotenoids are hydrolyzed in the duodenum by enzymes to form micelles in the small intestine for absorption 4. Stored in the liver 5. Figures and Tables a. Figure 10.2 – central cleavage of β-carotene to retinal b. Figure 10.3 – digestion and absorption of carotenoids and vitamin A, and re-esterification of retinol in the small intestine c. Figure 10.4 – retinoid metabolism C. Transport, Metabolism, and Storage 1. Transport to tissue requires newly formed retinyl esters to be incorporated into chylomicrons, which enter first into the lymphatic system and then into general circulation via the thoracic duct 2. Small quantities of unesterified retinol may enter portal blood 3. Retinyl esters are hydrolyzed by retinyl ester hydrolase following their uptake by hepatic parenchymal cells; within the hepatic cell, retinol binds to cellular retinol-binding protein, found throughout the body 4. Retinol that has been esterified may be stored in the liver; small amounts of retinol are stored in parenchymal cells 5. Retinol transport in the blood requires two specific proteins: retinol-binding protein and transthyretin 6. Retinol uptake is mediated by the protein transporter and stimulated by retinoic acid 6 7. Carotenoids reaching the liver undergo metabolism for either storage, cleavage, and/or incorporated into very low-density lipoproteins 8. Key Terms a. Parenchymal cells – functional cells of an organ such as the liver b. Stellate cells – storage cells of the liver 9. Figures and Tables a. Figure 10.5 – vitamin A metabolism in the liver D. Functions and Mechanisms of Action 1. Vitamin A is essential for vision as well as for cellular differentiation, growth, reproduction, bone development, and immune system functions 2. Key Terms a. Rhodopsin – a vitamin A-containing protein found in the eye b. Transducin – a G-protein found in the eye that responds to changes in opsin and is involved in the visual cycle c. Homodimers – complexes formed between two of the same receptors or molecules © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

d. Heterodimers – complexes formed between two or more different receptors or molecules e. Keratinocytes – cells that produce the protein keratin f. Osteoblasts – bone-forming cells g. Osteoclasts – cells that break down or resorb bone 3. Figures and Tables a. Figure 10.6 – an overview of the role of vitamin A as a part of rhodopsin in vision b. Figure 10.7 – the visual cycle c. Figure 10.8 – photoreceptor cells, their structure, and their surroundings d. Figure 10.9 – hypothesized mode of action for retinoic acid on gene expression E. Interactions with Other Nutrients 1. Vitamin A and carotenoids interact with vitamins E and K 2. Excess vitamin A interferes with vitamin K and high β-carotene intake may decrease plasma vitamin E concentrations 3. Figures and Tables a. Figure 10.10 – metabolism of vitamin A, showing some excretory products that are secreted into the bile for removal from the body F. Metabolism and Excretion 1. Vitamin A is excreted in both the urine and feces 2. Carotenoids are metabolized and excreted primarily into the bile for fecal elimination G. Recommended Dietary Allowance 1. Vitamin A recommendation for adult men is 900 µg per day and 700 µg per day for adult women H. Deficiency 1. Vitamin A deficiency is rare in the United States 2. Selected signs and symptoms include anorexia, retarded growth, increased susceptibility to infections, obstruction and enlargement of hair follicles, and keratinization of epithelial cells 3. Key Terms a. Xerophthalmia – dryness of the conjunctiva and keratinization of the epithelium of the eye following inflammation of the conjunctiva associated with vitamin A deficiency b. Bitot’s spots – small, white, foamy-looking accumulations of sloughed cells and secretions in the eye that are associated with a vitamin A deficiency I. Toxicity 1. The Tolerable Upper Limit Level for vitamin A is 3,000 µg per day. Ingesting larger amounts may result in acute hypervitaminosis A with symptoms of nausea, vomiting, double or blurred vision, increased intracranial pressure, headache, dizziness, diarrhea, skin desquamation, and muscle incoordination 2. Key Terms © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

a. Hyperplasia – abnormal cell proliferation b. Teratogenic – capable of causing birth defects in a fetus J. Assessment of Nutriture 1. To assess for night blindness, electrophysiological measurements directly measure the level of rhodopsin and its rate of regeneration in the eye 2. Conjunctival impression cytology is used to detect other eye problems 3. Plasma retinol concentrations are recommended as a biochemical indicator of vitamin A; relative dose response test is used to measure amounts of vitamin A in the liver III. Vitamin D 1. Vitamin D was discovered in 1922 and is derived from a steroid and considered to be a seco-steroid because one of its four rings is broken A. Sources 1. Vitamin D is provided as D3 by a relatively small number of foods of animal origin 2. The largest quantities are found in fatty fish; a few plant-origin foods provide some vitamin D as D2 3. Figures and Tables a. Table 10.4 – vitamin D content of selected foods b. Figure 10.11 – production of ergocalciferol and vitamin D3 B. Absorption 1. Dietary vitamin D requires no digestion and is absorbed from a micelle by passive diffusion into the intestinal cell C. Transport, Metabolism, and Storage 1. Chylomicrons transport vitamin D that came from the diet to nonhepatic tissues throughout the body, and deliver the vitamin to the liver 2. Vitamin D3 is made in the skin, which slowly diffuses from the skin and is picked up for transport in the blood by a vitamin D-binding protein 3. Vitamin D reaching the liver must be hydroxylated by cytochrome P-450 hydroxylases; after hepatic synthesis, most 25-OH D is secreted from the liver and transported in the blood by DBP and taken up by most tissues 4. Figures and Tables a. Figure 10.12 – hydroxylation of vitamin D D. Functions and Mechanisms of Action 1. Calcitriol is mostly recognized for its role in serum calcium homeostasis with effects on the kidneys, small intestine, and bone; additional roles include serum phosphorus homeostasis; cell differentiation, proliferation, and growth; and muscle structure and function, as well as genomic mechanisms of action 2. Figures and Tables a. Figure 10.13 – proposed role of calcitriol bound to VDR on DNA in gene expression b. Figure 10.14 – calcitriol, 1,25-(OH)2D, synthesis and actions with parathyroid hormone © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

E. Interactions with Other Nutrients 1. Vitamin D interacts with calcium and phosphorus, as well as vitamin K F. Metabolism and Excretion 1. Calcitroic acid and vitamin D metabolites are excreted through the bile in the feces, with a little excreted via the urine

G. Recommended Dietary Allowance 1. Vitamin D recommendation is 600 IU for children older than 1 year, adolescents, and adults; this amount increases to 800 IU at the age of 70 and over H. Deficiency: Rickets and Osteomalacia 1. Vitamin D most notably affects bone. In infants and young children, the deficiency causes rickets, characterized by failure of bone to mineralize 2. In adults, vitamin D deficiency leads to osteomalacia 3. Key Terms a. Osteomalacia – a disorder characterized by bone-mineralization defects that may occur in adults because of inadequate vitamin D intake I. Toxicity 1. The Tolerable Upper Intake Level has been set at 4,000 IU, by the Institute of Medicine, for children 9 years and older, adolescents, and adults 2. The Endocrine Practice Guidelines Committee sets the Upper Tolerable Intake Level at 10,000 IU J. Assessment of Nutriture 1. Serum 25-OH D concentrations are most often used to asses vitamin D status; concentrations less than 20 ng/mL indicate deficiency IV. Vitamin E 1. Vitamin E encompasses eight compounds (vitamers), each containing a phenolic functional group on a chromanol ring; discovered in 1922 2. Key Terms a. Phytyl tail – refers to the structure of the side chains of vitamins E and K 3. Figures and Tables a. Figure 10.15 – structures of the various forms of the tocopherols and tocotrienols A. Sources 1. Vitamin E is found primarily in plant foods, especially nuts, foods made from nuts, seeds, and the oils from plants 2. Figures and Tables a. Table 10.5 – vitamin E content of selected foods B. Digestion and Absorption 1. Tocopherols are found free in foods and tocotrienols are found esterified and must be hydrolyzed before absorption 2. Vitamin E is absorbed primarily in the jejunum by passive diffusion C. Transport, Metabolism, and Storage 1. In the enterocyte, the absorbed tocopherols and tocotrienols are incorporated into chylomicrons for transport through the lymph and then into circulation 2. Hepatic uptake of vitamin E occurs following delivery of the tocopherols and tocotrienols via chylomicron remnants 3. Tocopherol uptake into cells occurs in association with lipoproteins and vitamin E binds to specific binding proteins for intracellular transport © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

4. There is no single storage organ for vitamin E D. Functions and Mechanisms of Action 1. Vitamin E has a principal function as an antioxidant 2. Figures and Tables a. Figure 10.16 – initiating and chain reactions caused by hydroxyl-free radical attack on unsaturated fatty acid b. Figure 10.17 – regeneration of vitamin E E. Interactions with Other Nutrients 1. There is an interrelationship between vitamin E and selenium, vitamin E and vitamin C, vitamin E and β-carotene, and vitamin E and vitamin K F. Metabolism and Excretion 1. Hepatic metabolism of vitamin E begins with ω-hydroxylation reaction to form hydroxychromanol, followed by β-oxidation of fatty acids to create phytyl side chains 2. Vitamin E is excreted via the urine and feces G. Recommended Dietary Allowance 1. Vitamin E recommendation is 15 mg for adult men and women H. Deficiency 1. A vitamin E deficiency is rare, but if seen may impact the integrity of cell membranes I. Toxicity 1. Vitamin E appears to be the least toxic fat-soluble compound with a Tolerable Upper Intake Level of 1,000 mg of α-tocopherol for adults J. Assessment of Nutriture 1. Blood analysis is used to evaluate vitamin E; concentrations <5 mg/L suggest deficiency and >20 mg/L suggest possible toxicity V. Vitamin K 1. Discovered in 1935. Compounds with vitamin K activity have a 2-methyl 1, 4-naphthoquinone ring with a substitution at position 3 2. Figures and Tables a. Figure 10.18 – structures of vitamin K A. Sources 1. Dietary vitamin K is provided mostly as phylloquinone from ingestion of plant foods 2. Figures and Tables a. Table 10.6 – vitamin K content of selected foods B. Absorption 1. Phylloquinone requires no digestion and is absorbed from the small intestine, particularly the jejunum C. Transport, Metabolism, and Storage 1. Within the enterocytes, the phylloquinone is incorporated into chylomicrons that enter the lymphatic system and then the circulatory system for transport to tissues

2. Any remaining vitamin K is delivered to the liver for metabolism and is then incorporated into very low-density lipoproteins for secretion into the blood and transport to extrahepatic tissues

D. Functions and Mechanisms of Action 1. Functions in blood clotting, bone mineralization, apoptosis, growth, and signal transduction 2. Key Terms a. Hydroxyapatite – a crystal lattice-like substance with the formula Ca10(PO4)6(OH)2; found in bones and teeth 3. Figures and Tables a. Figure 10.19 – an overview of blood clotting b. Figure 10.20 – production of s-carboxylglutamic acid via vitamin Kdependent carboxylation c. Figure 10.21 – the vitamin K cycle E. Interactions with Other Nutrients 1. Vitamin A and E are known to antagonize vitamin K F. Metabolism and Excretion 1. Phylloquinone is almost completely metabolized to a variety of metabolites before being excreted 2. Most phylloquinone’ s metabolites are conjugated with glucuronic acid for excretion mostly in the feces with some in the urine G. Adequate Intake 1. Vitamin recommendations for adult males is 120 µg/day and 90 µg/day for adult females H. Deficiency 1. Vitamin K deficiency is rare but subclinical deficiencies have been seen with provisions of about 10 g daily of phylloquinone. Severe deficiency is associated with bleeding episodes I. Toxicity 1. No Tolerable Upper Limit Level has been established for vitamin K J. Assessment of Nutriture 1. Multiple biomarkers are used to assess vitamin K since no single index or biomarker clearly indicates deficiency and adequacy 2. Plasma and serum levels may be used to reflect phylloquinone levels, prothrombin time measures the time required for a fibrin clot to form, and a measurement of the percentage of undercarboxylated vitamin Kdependent proteins

Resources Suggested Readings • Demmig-Adams B, Adams RB. Eye nutrition in context: mechanisms, implementation, and future directions. Nutrients. 2013; 5:2483–2501. • Grune T, Lietz G, Palou A, et al. β-carotene is an important vitamin A source for humans. J Nutr. 2010; 140:S2268–85. • Noy N. Between death and survival: retinoic acid in regulation of apoptosis. Ann Rev Nutr. 2010; 30:201–18.

• • • • •

Sommer A. Vitamin A deficiency and clinical disease: an historical overview. J Nutr. 2008; 138:1835–39. Carr AC, Vissers MCM. Synthetic or food-derived vitamin C—are they equally bioavailable? Nutrients. 2013; 5:4284–4304. Ceglia L. Vitamin D and skeletal muscle tissue and function. Molec Aspects Med. 2008; 29:407–14. Fry CM, Sanders TAB. Vitamin D and risk of CVD: a review of the evidence. Proc Nutr Soc. 2015; doi:10.1017/S00029665115000014. Grant WB. In defense of the sun an estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermatoendocrinol. 2009; 1:207–14. Pourshahidi LK. Vitamin D and obesity: current perspectives and future directions. Proc Nutr Soc. 2014; doi:10.1017/S0029665114001578. Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene. 2015; 561:171–80. vanEtten E, Stoeffels K, Gysemans C, et al. Regulation of vitamin D homeostasis: implications for the immune system. Nutr Rev. 2008; 66(suppl 2):S125-34. Niki E, Traber MG. A history of vitamin E. Ann Nutr Metab. 2012;61:207–12. Vermeer C. Vitamin K: the effect on health beyond coagulation—an overview. Food Nutr Res. 2012; 56:doi:10.3402/fnr.v56i1.5329.

Additional Resource •

Tsugawa, N. (2015). Cardiovascular diseases and fat soluble vitamins: vitamin D and vitamin K. Journal of Nutritional Science and Vitaminology, S170-S172. Article ID Cardiovascular diseases and fat soluble vitamins: vitamin D and vitamin K

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

What are the biochemical or physiological functions of each of the fat-soluble vitamins and which processes would be affected if the body was low in that vitamin?

•

Discuss the system/sites of each fat-soluble vitamin. • Vitamin A – skin, skeletal bone, ocular • Vitamin D – muscle and skeletal bone • Vitamin K – skeletal bone and blood vessels/cells • Vitamin E – blood vessels/cells and ocular

Assignment – Individual Paper •

Vitamin A has a role in the vision cycle. Cover the steps of the vision cycle in either a figure or a step-by-step list.

Answer Keys Worksheet 1: Responding to Research – Fat-Soluble Vitamins and Cardiovascular Effects 1. b 2. b 3. reduce 4. It may be measured through the serum proteins by measuring the protein induced by vitamin K absence II, the undercarboxylated OC, and the uncarboxylated MGP. Worksheet 2: Nutrition Lab – Fat-Soluble Meal Plan 1. Meal plan will vary by student. 2. Vitamin A RDA = 900 µg for adult males; 700 µg for adult females 3. Vitamin D RDA = 15–20 µg 4. Vitamin E RDA = 15 mg α-tocopherol 5. Vitamin K RDA = 120 µg for adult males; 90 µg for adult females

Worksheet 1: Research Study – Fat-Soluble Vitamins and Cardiovascular Effects Cardiovascular disease affects many and much of the diet affects the condition of heart and vessels. It is usually thought that fats cause cardiovascular disease but there are other causes, including poor nutrition. Read the following article and then respond to the questions. • Tsugawa, N. (2015). Cardiovascular diseases and fat soluble vitamins: vitamin D and vitamin K. Journal of Nutritional Science and Vitaminology, S170-S172. Article ID Cardiovascular diseases and fat soluble vitamins: vitamin D and vitamin K 1. This journal report has proven that fat-soluble vitamin supplementation reduces the risk of cardiovascular disease. a. True b. False __________ 2. Avery is concerned with developing cardiovascular disease because it runs heavily in her family. She wants to make sure she has a balanced diet and is considering taking a vitamin supplement. She is wondering if there is a fat-soluble vitamin whose deficiency has shown an increase in cardiovascular disease. a. No, there is no study that shows any fat-soluble vitamin deficiency leads to an increase. b. Yes, vitamin D and vitamin K deficiency have shown an increase. c. Yes, but only vitamin D deficiency has shown an increase. d. No, only water-soluble vitamin deficiency has shown to cause an increase. __________ 3. Vitamin D has shown to __________ lesions caused by plaque. a. reduce b. increase c. not affect __________ 4. How is vitamin K deficiency measured?

Worksheet 2: Nutrition Lab – Fat-Soluble Meal Plan Meal plans help keep us on a balanced diet and help reassure we get the necessary nutrients, including fat-soluble vitamins. 1. Create a meal plan for a day, including three meals with two snacks. The meal plan must contain the recommended dietary allowance for all the fat-soluble vitamins. Also, distinguish if your meal plan is for an adult male or adult female.

2. What is the RDA for vitamin A? What is the amount of vitamin A in your created meal plan?

3. What is the RDA for vitamin D? What is the amount of vitamin D in your created meal plan?

4. What is the RDA for vitamin E? What is the amount of vitamin E in your created meal plan?

5. What is the RDA for vitamin K? What is the amount of vitamin K in your created meal plan?

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 11 – Major Minerals Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Research Study – Calcium and Phosphorus Homeostasis Worksheet 2: Labeling It – PTH and Calcium Regulation

Chapter Outline I. Introduction 1. This chapter covers the major minerals such as calcium, phosphorus, magnesium, sodium, potassium, and chloride, which constitute about 4% of the total body weight. 2. Minerals are inorganic elements that come from the earth 3. Major minerals are required in the adult in amounts greater than 100 mg/day 4. Key Terms a. Ions – an electrically charged atom or group of atoms; positively charged ions are called cations, and negatively charged ions are called anions 5. Figures and Tables a. Figure 11.1 – the periodic table highlighting the body’s major minerals b. Table 11.1 – major minerals: functions, approximate body content, deficiency symptoms, food sources, and recommended dietary allowances II. Calcium 1. Most abundant divalent cation in the body, representing about 40% of the body’s mineral mass A. Sources 1. The best food sources of calcium are dairy products 2. Figures and Tables a. Table 11.2 – calcium content of selected foods B. Digestion, Absorption, and Transport 1. Calcium is available in foods as relatively insoluble salts; it takes 1 hour at an acidic pH for calcium to be solubilized from most calcium salts

2. Calcium absorption occurs in the small intestine via two mechanisms: (1) saturable, carrier-mediated, active, transcellular transport and (2) diffusion 3. Calcium absorption via active transport involves a channel protein called transient receptor potential vanilloid 6 4. Transcaltachia is a process of rapid absorption of calcium through calcium channels in the enterocyte’s brush border membrane 5. Calcium absorption is influenced by stage of life and dietary factors 6. Calcium is transported in the blood in three forms 7. Figures and Tables a. Table 11.3 – interactions between calcium and selected nutrients/substances b. Figure 11.2 – the binding of calcium by oxalic acid C. Regulation and Homeostasis 1. Calcium concentrations are regulated intracellularly and extracellularly 2. Three main hormones are involved in extracellular regulation: PTH, calcitriol, and calcitonin 3. Ionized calcium is removed from the blood with secretion into the digestive tract, excretion in the urine, and uptake by the tissues 4. Calcium gains entry into intracellular sites such as the endoplasmic reticulum and mitochondria 5. The efflux of organelle-sequestered calcium into the cytosol typically requires a Ca2+-ATPase pump or release channel 6. Calcium-binding proteins function as an important buffer within cells to prevent excessive free calcium 7. Key Terms a. Ryanodine receptor – a calcium channel in the sarcoplasmic reticulum of muscle that opens to permit the release of calcium 8. Figures and Tables a. Figure 11.3 – calcium digestion, absorption, and transport b. Figure 11.4 – an overview of blood calcium regulation by parathyroid hormone and calcitriol in response to low blood calcium concentrations c. Table 11.4 – summary of the effects of parathyroid hormone, calcitriol, and calcitonin on calcium balance D. Functions and Mechanisms of Action 1. Calcium plays major roles in bone mineralization, muscle contraction, blood clot formation, signal transduction, and enzyme activation 2. Figures and Tables a. Figure 11.5 – schematic representation of the structural change that occurs in calmodulin following the binding of calcium ions b. Table 11.5 – selected enzymes regulated by calcium and/or calmodulin E. Interactions with Other Nutrients 1. Large amounts of calcium along with phosphorus-containing foods inhibit phosphorus absorption 2. Calcium from dietary sources as well as supplements can decrease iron absorption; calcium also diminishes the absorption of fatty acids © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. Figures and Tables a. Figure 11.6 – some of calcium’s intracellular actions and mechanisms by which cytosolic calcium concentrations are maintained

F. Excretion 1. Calcium is excreted through the feces and urine 2. The kidneys filter ionized calcium and calcium that is bound to anions G. Recommended Dietary Allowances 1. Adult men, adult women, and pregnant and lactating women should consume 1,000 mg daily between the ages of 19 and 70 H. Deficiency 1. Inadequate intake of calcium, poor absorption, and excessive losses all contribute to calcium deficiency that also diminishes vitamin D absorption; this may lead to calcium loss from bone, osteopenia, muscle spasms, increased risks of colon cancer, type 2 diabetes mellitus, metabolic syndrome, and obesity 2. Key Terms a. Hypocalcemia – low concentration of calcium in the blood b. Tetany – a condition resulting from inadequate blood calcium concentrations, characterized by prolonged muscle contractions I. Toxicity 1. The Tolerable Upper Intake Level is 2,500 mg of calcium for adults between 19 and 50 years of age, decreasing to 2,000 mg at age 51 and older 2. Idiopathic hypercalciuria, as well as calcium-alkali syndrome, is a condition that may result from too much calcium consumption 3. Key Terms a. Hypercalciuria – excessive urinary calcium excretion J. Assessment of Nutriture 1. No routine biochemical method is available to directly assess calcium status 2. Serum calcium may be evaluated, or measuring bone mineral density III. Phosphorus 1. Phosphorus is the second most abundant mineral in the body, representing 0.8–1.4% of body weight A. Sources 1. Best food sources for phosphorus include protein-rich foods like meat 2. Figures and Tables a. Table 11.6 – phosphorus content of selected foods B. Digestion, Absorption, and Transport 1. Most phosphorus is absorbed from the gastrointestinal tract as free inorganic phosphate ions 2. Phosphorus absorption occurs throughout the small intestine, but primarily in the jejunum 3. Absorption occurs by two processes: (1) saturable, carrier-mediated, active transport and (2) diffusion 4. Active transport involves a sodium-phosphate cotransporter 5. Many factors influence phosphorus absorption, such as phosphorus bioavailability, magnesium, aluminum, calcium, and niacin © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

6. Phosphorus is quickly absorbed from the intestine and appears in the blood within an about an hour after ingestion 7. Figures and Tables a. Figure 11.7 – phytic acid b. Figure 11.8 – digestion, absorption, and transport of phosphorus C. Regulation and Homeostasis 1. Parathyroid hormone and fibroblast growth factor 23 influence phosphorus balance, with calcitriol and calcitonin contributing D. Functions and Mechanisms of Action 1. Phosphorus is found in all cells of the body and plays roles in bone mineralization, energy transfer and storage, nucleic acid formation, cell membrane structure, and acid-base balance 2. Figures and Tables a. Figure 11.9 – some examples of important phosphorus-containing compounds in the body E. Excretion 1. Phosphorus is excreted via the urine and feces F. Recommended Dietary Allowance 1. For adult males and females, it is recommended to obtain 700 mg/day of phosphorus G. Deficiency 1. Phosphorus deficiency is rare, but if present affects bone and severe deficiency could affect oxygen transport and cardiac output, and cause arrhythmias, skeletal muscle and cardiac myopathy, and neurological problems H. Toxicity 1. The Tolerable Upper Intake Level is 4 g of phosphorus for ages 9 to 70 2. Toxicity may impair renal function, and cause atherosclerosis and left ventricular hypertrophy I. Assessment of Nutriture 1. Serum concentration and urinary excretion may be assessed for phosphorus levels IV. Magnesium 1. Magnesium ranks sixth in overall abundance in the body out of the major minerals A. Sources 1. Magnesium is found in a variety of foods, including nuts, seeds, and wholegrain cereals 2. Figures and Tables a. Table 11.7 – magnesium content of selected foods B. Digestion, Absorption, and Transport 1. Dietary magnesium doesn’t require digestion prior to absorption 2. Two processes facilitate magnesium absorption throughout the small intestine; however, the colon also absorbs magnesium © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. The two small intestine processes are (1) saturable, carrier-mediated active transport and (2) diffusion 4. The active transporter required for magnesium is a transient receptor protein melastatin divalent cation-permeable channel protein; in the plasma/serum, most magnesium is found free in its ionic form as magnesium cation, 20–30% is bound to protein, and 5–15% is complexed with citrate, phosphate, sulfate, or other negative charged anions 5. Figures and Tables a. Figure 11.10 – magnesium absorption and transport b. Table 11.8 – substances/nutrients affecting intestinal magnesium absorption C. Regulation and Homeostasis 1. Magnesium balance depends on gastrointestinal absorption and renal excretion 2. Plasma magnesium concentrations can be maintained at the expense of the bone D. Functions and Mechanisms of Action 1. Magnesium aids in bone mineralization, enzymatic reactions, nucleic acids, platelet activity, hormone receptor binding and signaling transmission, cell membrane ion transfer, and calcium regulation 2. Figures and Tables a. Figure 11.11 – modes by which Mg2+ provides stability to ATP E. Interactions with Other Nutrients 1. Magnesium interacts with phosphorus to inhibit phosphorus absorption. Magnesium also interacts with potassium F. Excretion 1. Magnesium is excreted from the body mainly via the kidneys, with lesser amounts excreted in the urine when plasma magnesium is low G. Recommended Dietary Allowance 1. The RDA for magnesium for adult males between 19 and 30 years of age is 400 mg and females needing 310 mg; above 31 years of age, males should have 420 mg and females 320 mg 2. During pregnancy between 19 and 30 years, it is 350 mg and for 31–50 years, it is 360 mg; during lactation for 19–30 years, it is 310 mg and for 31–50 years, it is 320 mg H. Deficiency 1. Magnesium deficiency is traditionally diagnosed based on total plasma/serum magnesium concentrations 2. Hypomagnesemia can include decreased serum concentrations of PTH, calcium, potassium, and calcitriol 3. Symptoms may include neuromuscular hyperexcitability 4. Key Terms a. Hypokalemia – low concentrations of potassium in the blood I. Toxicity

1. Excessive intake of magnesium from food sources has not been shown to cause toxicity in health individuals 2. The Tolerable Upper Intake Level of 350 mg of magnesium from nonfood sources has been recommended for people age 9 years and older 3. Excessive intake may lead to cathartic effect, nausea, vomiting, depression, muscle weakness, and paralysis J. Assessment of Nutriture 1. Plasma/serum concentrations may be measured to test magnesium levels

Resources Suggested Readings • Golden NH, Abrams SA, Committee on Nutrition. Optimizing bone health in children and adolescents. Pediatr. 2014; 134:e1229–43. • Hoenderop JGJ, Nilius B, Bindels RJM. Calcium absorption across epithelia. Physiol Rev. 2005; 85:373–422. • Patel AM, Gbemisola AA, Goldfarb S. Calcium-alkali syndrome in the modern era. Nutrients. 2013; 5:4880–93. • Straub DA. Calcium supplementation in clinical practice: a review of forms, doses, and indications. Nutr Clin Pract. 2007; 22:286–96. • Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Ann Rev Nutr. 2010; 61:91–104. • Calvo MS, Moshfegh AJ, Tucker KL. Assessing the health impact of phosphorus in the food supply: issues and considerations. Adv Nutr. 2014; 5:104–13. • Ellam TJ, Chico TJA. Phosphate: the new cholesterol? The role of the phosphate axis in non-uremic vascular disease. Atherosclerosis. 2012; 220:310–18. • Del Gobbo LC, Imamura F, Wu JH, de Oliveira Otto MC, Chiuve SE, Mozaffarian D. Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2013; 98:160–73. • Duley L, Matar HE, Almerie MQ, Hall DR. Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia. Cochrane Database Syst Rev. 2010; 8:CD007388. • Rosanoff A, Weaver CM, Rude RK. Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr Rev. 2012; 70:153–64. • Volpe SL. Magnesium in disease prevention and overall health. Adv Nutr. 2013; 4:378S–83S. • Xu T, Sun Y, Xu T, Zhang Y. Magnesium intake and cardiovascular disease mortality: a meta-analysis of prospective cohort studies. Int J Cardiol. 2013; 167:3044–7. Additional Resource •

Shaker JL, Deftos L. Calcium and phosphate homeostasis. [Updated 2014 Apr 11]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Article ID Calcium and phosphate homeostasis

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. • What are the physiological functions of each of the three major minerals discussed in this chapter?

•

Discuss the deficiency symptoms of each of the three major minerals discussed in this chapter. • Calcium – rickets, osteoporosis, tetany • Phosphorus – neuromuscular, skeletal, hematological, and cardiac manifestations; rickets, osteomalacia • Magnesium – neuromuscular hyperexcitability, cardiovascular effects, central nervous system effects

Assignment – Individual Paper •

Calcium and phosphorus have primary roles in bone health. Discuss what deficiencies are caused by a lack of calcium, phosphorus, and/or both. Discuss how the two minerals interact to achieve bone health. Discuss ways to prevent deficiency of the two minerals. o To prevent deficiencies of either mineral, the RDA should be consumed daily through suggested foods for each mineral.

Answer Keys Worksheet 1: Responding to Research – Calcium and Phosphorus Homeostasis 1. b 2. d 3. inhibits; excretion 4. Osteoporosis is when bone density decreases and osteomalacia is when bone density increases. Worksheet 2: Labeling It – PTH and Calcium Regulation 1. Low blood calcium signals the parathyroid gland to release parathyroid hormone into the blood. 2. PTH binds to bone cell receptors and triggers the resorption or breakdown of bone mineral for the release of calcium into the blood. 3. PTH acts on the kidneys to synthesize the active form of vitamin D, calcitriol. 4. PTH and calcitriol promote the reabsorption of calcium from the kidneys and into the blood. 5. Calcitriol leaves the kidneys and travels to the intestine, where it promotes calcium absorption across the brush border membrane, its transport in the cell cytosol, and egress into the blood. 6. Calcium enters the blood; a – after release from bone, b – after release from kidneys, and c – after absorption from intestinal cells.

Worksheet 1: Research Study – Calcium and Phosphorus Homeostasis Calcium and phosphorus are required for many functions within the body, especially bone health. Both minerals interrelate to provide bone health. It is vital to keep both major minerals in balance through the daily diet and supplementation. Read the following article and then respond to the questions. • Shaker JL, Deftos L. Calcium and phosphate homeostasis. [Updated 2014 Apr 11]. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000. Article ID Calcium and phosphate homeostasis 1. High levels of PTH decrease osteoclastic bone resorption. a. True b. False __________ 2. What is the effect of the parathyroid hormone on calcium and skeletal metabolism? a. Kidneys increase resorption. b. Blood increases calcium and phosphorus absorption. c. Bone increases phosphorus excretion. d. Gastrointestinal tract increases calcium and phosphorus absorption. __________ 3. Calcitonin __________ the reabsorption of phosphate through the kidneys, which then leads to __________ of renal phosphate. a. increases; absorption b. inhibits; absorption c. inhibits; excretion __________ 4. What is the difference between osteoporosis and osteomalacia?

Worksheet 2: Labeling It – PTH and Calcium Regulation Using the figure below, list the steps of blood calcium regulation by the parathyroid hormone.

1. 2. 3. 4. 5. 6. a. b. c.

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 12 – Water and Electrolytes Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Labeling It Worksheet 1: Responding to Research – Potassium and Blood Pressure Worksheet 2: Labeling It – Organs Effects on Fluid Balance

Chapter Outline I. Introduction 1. Water accounts for about 60% of an adult’s total body weight and is vital for life II. Water Functions 1. Water has many critical roles in the body including: chemical reactions, body temperature regulation, lubrication and protection, solvent and transport medium, maintenance of blood volume, and acid-base balance III. Body Water Content and Distribution 1. Body water contributes typically over one-half of a person’s body weight, with distribution varying based on age, body size, and body composition 2. Figures and Tables a. Table 12.1 – body fluid compartments b. Table 12.2 – electrolyte composition of body fluids IV. Water Losses, Sources, and Absorption 1. Water is lost from the body each day primarily through the urine, lesser amounts excreted in the feces, with additional losses to body functions V. Recommended Water Intake 1. Intake varies based on age, gender, environment, physical activity, and rate of metabolism; the adequate intake for an adult female is 2.7 liters and for an adult male is 3.7 liters

VI. Water (Fluid) and Sodium Balance A. Osmotic Pressure 1. Pressure that affects water passage across the cell plasma membrane between the intracellular and extracellular compartments; gains and losses of fluid along with the solutes (salts) influence fluid balance and flow 2. Key Terms a. Osmosis – the net movement of the solvent from a solution of lesser concentration to one of greater concentration when the two solutions are separated by a membrane that selectively prevents passage of solute molecules but is permeable to the solvent b. Hyponatremia – low concentrations of sodium in the blood 3. Figures and Tables a. Figure 12.1 – electrolytes in the plasma, interstitial, and intracellular compartments of the body B. Hydrostatic Pressure 1. Pressure that affects water movement within the two main extracellular fluid compartments, between the interstitial fluid and the plasma 2. Water moves from areas of higher pressure to areas of lower pressure, known as hydrostatic pressure 3. Figures and Tables a. Figure 12.2 – Starling’s hypothesis of water distribution between plasma and interstitial fluid compartments C. Colloidal Osmotic Pressure 1. This is the pressure that affects water movement across the capillary walls that separate the plasma and the interstitial fluid 2. Key Terms a. Colloids – substances comprised of very small particles that are suspended uniformly in a medium D. Extracellular Fluid Volume and Osmolarity and Hormonal Controls 1. Shifts in the extracellular fluid volume and osmolarity serve as one of the many triggers for the release of hormones responsible for correcting imbalances; these hormones include vasopressin, renin-angiotensinaldosterone system, and natriuretic peptides 2. Key Terms a. Osmolality – a measure of solute particle numbers expressed as osmoles of solute per kg of solvent b. Osmoles – the number of moles of each particle in solution c. Natriuresis – excretion of large amounts of sodium in the urine 3. Figures and Tables a. Figure 12.3 – a nephron b. Figure 12.4 – the effects of vasopressin and the renin-angiotensinaldosterone system on water and sodium balance

VII. Sodium A. Sources 1. The major source of sodium in the diet of Americans is salt. Naturally occurring sources are milk, meat, eggs, and most vegetables B. Absorption and Transport 1. The majority of sodium is absorbed from the small intestine and proximal portion of the colon 2. Three main mechanisms enable intestinal sodium absorption: (1) Na+/glucose cotransporter, (2) electroneutral Na+ and Cl- cotransport exchange, and (3) electrogenic system; sodium is then transported freely in the blood 3. Figures and Tables a. Figure 12.5 – intestinal sodium absorption C. Functions and Interactions with Other Nutrients 1. Sodium plays important roles in maintaining osmotic pressure for fluid balance and aids in nerve transmission/impulse conduction and muscle contraction D. Excretion 1. Kidneys provide the primary means of excreting excess sodium E. Adequate Intake, Deficiency, Toxicity, and Assessment of Nutriture 1. Sodium intake is recommended at an Adequate Intake of 1,500 mg and a Tolerable Upper Intake Level of 2,300 mg for adults daily 2. Dietary deficiency of sodium doesn’t normally occur; however, excessive sweating may result in deficiency 3. Deficiency symptoms include muscle cramps, nausea, vomiting, dizziness, shock, and coma 4. Sodium is measured via a 24-hour urinary sodium excretion level VIII. Potassium A. Sources 1. Potassium is widespread in the diet and abundant in fruits and vegetables. Potassium may also be found in processed foods B. Absorption and Transport 1. Over 85% of ingested potassium is absorbed and absorption occurs throughout the small intestine and lesser in the colon, usually via passive diffusion C. Functions and Interactions with Other Nutrients 1. Potassium has roles in water balance, acid-base balance, and cellular metabolism 2. Potassium interacts with calcium and affects urinary excretion of calcium D. Excretion 1. Potassium is excreted from the body mainly via the kidneys with small amounts through the feces and sweat E. Adequate Intake, Deficiency, Toxicity, and Assessment of Nutriture 1. Adequate Intake of potassium is 4,700 mg per day for adults © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Deficiency of potassium is seen from situations causing loss of fluids and electrolytes; deficiency symptoms include muscle weakness, lethargy, ascending paralysis, cardiac arrhythmias, and possibly death 3. Key Terms a. Hyperkalemia – high concentrations of potassium in the blood IX. Chloride A. Sources 1. Most chloride consumed in the diet is associated with sodium chloride, and abundant in many foods, including snack items and processed foods; it is also found in eggs, fresh meats, and seafood B. Absorption and Transport 1. Chloride is almost completely absorbed in the intestines and follows that of sodium for the establishment and maintenance of electrical neutrality and osmotic balance 2. In the electroneutral Na+/Cl- cotransport absorption system, chloride is absorbed in exchange for bicarbonate as sodium is absorbed in exchange for H+; Cl- channels in colonic cells also provide for chloride transport 3. Figures and Tables a. Figure 12.6 – one mechanism for intestinal chloride secretion C. Functions and Interactions with Other Nutrients 1. Chloride aids in fluid balance, formation of gastric hydrochloric acid, destruction of foreign substances, and chloride shift D. Excretion 1. Chloride excretion occurs through three routes: (1) the gastrointestinal tract, (2) the skin, and (3) the kidneys E. Adequate Intake, Deficiency, Toxicity, and Assessment of Nutriture 1. Adequate Intake recommendation for chloride for adults is 2,300 mg per day with a Tolerable Upper Intake Level of 3.6 g 2. If dietary deficiency occurs, symptoms are diarrhea and vomiting resulting in weakness, lethargy, and metabolic acidosis 3. Chloride status is assessed through evaluation of chloride concentration in the serum X. Acid-Base Balance: Control of Hydrogen Ion Concentration 1. The maintenance of hydrogen ion concentration in body fluids 2. Key Terms a. Hydrogen ion – cation of hydrogen containing a single proton and no electrons A. Chemical Buffer Systems 1. A buffer is a substance that reversibly binds protons to help resist changes in pH despite the addition of acids or bases to the environment 2. The body has a bicarbonate-carbonic acid buffer system, a buffer system of proteins and hemoglobin, a phosphate buffer system, and a potassium buffer system © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

3. Key Terms a. Amphoteric – capable of reacting as either an acid or a base 4. Figures and Tables a. Figure 12.7 – red blood cell of hemoglobin as a buffer for hydrogen ions and the release of the buffer bicarbonate B. Respiratory Regulation 1. Lungs respond within minutes to unbalanced chemical buffer systems. They work to regulate the HCO3-/H2CO3 system C. Renal Regulation 1. Kidneys take hours or days to effect change in pH. They act by controlling the secretion of H+, by conserving or producing HCO3-, and by synthesizing and excreting ammonia, which reacts with H+ to form ammonium ions for excretion 2. Filtered phosphate also facilitates H+ excretion 3. Figures and Tables a. Figure 12.8 – acid-base balance by the kidneys XI. Summary A. Maintaining body fluids is a requirement for life B. Intracellular fluid provides the environment for metabolic reactions within cells, while the interstitial fluid compartment of the extracellular fluid allows nutrients to migrate from cells to the bloodstream C. Kidneys aid in fluid control mostly through hormones, with macrominerals aiding in fluid balance and waste removal

Resources Suggested Readings • Edwards JC. Chloride transport. Comprehensive Physiol. 2012; 2:1061–92. • Giebisch GH, Wang WH. Potassium transport—an update. J Nephrol. 2010; 23:S97–S104. • Hew-Butler T, Rosner MN, Fowkes-Godek S, et al. Statement of the third international exercise-associated hyponatremia consensus development conference, Carlsbad, California, 2015. Clin J Sport Med. 2015; 25:303–20. • Young JH, McDonough AA. Recent advances in understanding integrative control of potassium homeostasis. Ann Rev Physiol. 2009; 71:381–401. • Golden NH, Abrams SA, Committee on Nutrition. Optimizing bone health in children and adolescents. Pediatr. 2014; 134:e1229–43. Additional Resource •

Ellison, D. H., & Terker, A. S. (2015). Why your mother was right: how potassium intake reduces blood pressure. Transactions of the American Clinical and Climatological Association, 126, 46–55. Why your mother was right: how potassium intake reduces blood pressure

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

What are the body fluid compartments and approximate percentages of body weight of each?

•

What happens when the fluid levels decrease or increase in the different body fluid compartments? o Water movements are regulated by osmotic pressure. Differences in hydrostatic pressure and colloidal osmotic pressure will govern the movement of water. Using the different pressures, hormonal controls, kidneys, liver, lungs, adrenal cortex, and hypothalamus, the levels are restored.

Assignment – Individual Paper •

Kidneys play a major role in the acid-base balance. Using Figure 12.8, discuss the steps required to maintain this balance and how the kidneys aid in this role.

Answer Keys Worksheet 1: Responding to Research – Potassium and Blood Pressure 1. a 2. a 3. dependent 4. The high salt/normal K+ has a lower phosphorylated NaCl cotransporter compared to the high-salt/low-potassium diet. Worksheet 2: Labeling It – Organs Effects on Fluid Balance 1. Angiotensinogen – generates angiotensin I, which then produces angiotensin II that affects the sodium and water balance and blood pressure 2. ACE – angiotensin-converting enzyme 3. Aldosterone – promotes reabsorption of sodium and the excretion of potassium 4. Renin – releases when blood pressure and plasma fluid volumes are reduced and results in the release of aldosterone 5. Vasopressin – stimulates reabsorption of water in the kidneys, thirst, and vasoconstriction of the arterioles

Worksheet 1: Responding to Research – Potassium and Blood Pressure High blood pressure increases risks of cardiovascular disease. The American diet is filled with processed foods that contain high concentrations of NaCl. Sodium and chloride are both necessary minerals, but both have Tolerable Upper Intake Levels. Read the following article, and then respond to the questions. • Ellison, D. H., & Terker, A. S. (2015). Why your mother was right: how potassium intake reduces blood pressure. Transactions of the American Clinical and Climatological Association, 126, 46–55. Why your mother was right: how potassium intake reduces blood pressure 1. Potassium deficiency increases blood pressure. a. True b. False __________ 2. Tony wants to decrease his blood pressure through his diet prior to being put on prescription medications. His blood pressure is elevated, but not yet diagnosed as high blood pressure. What method should he implement in his diet? a. Increase KCl consumption and decrease NaCl consumption. b. Increase both KCl and NaCl consumption. c. Decrease both KCl and NaCl consumption. d. Decrease KCl consumption and increase NaCl consumption. __________ 3. The effects of potassium are __________ on the NaCl cotransporter. a. independent b. independent and dependent c. dependent __________ 4. What are the effects on the urinary phosphorylated NaCl cotransporter by the highsalt/normal K+ diet and the high-salt/low-potassium diet?

Worksheet 2: Labeling It – Organs Effects on Fluid Balance Using the figure below, list the hormones produced by each organ and the function of each hormone.

1. What hormone is produced by the liver? What is the effect of the hormone?

2. What hormone is produced by the lungs? What is the effect of the hormone?

3. What hormone is produced by the adrenal cortex? What is the effect of the hormone?

4. What hormone is produced by the juxtaglomerular apparatus? What is the effect of the hormone?

5. What hormone is produced by the hypothalamus? What is the effect of the hormone?

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 13 – Essential Trace and Ultratrace Minerals Table of Contents • • • • •

• •

Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Iron and Restless Leg Syndrome Worksheet 2: Nutrition Lab – ATP7B in Copper Use

Chapter Outline I. Introduction 1. These are elements that are needed by the body in small amounts, less than 100 mg/day 2. Figures and Tables a. Figure 13.1 – periodic table highlighting some of the essential trace and ultratrace elements b. Table 13.1 – approximate body content, selected functions, deficiency symptoms, food sources, and recommended dietary allowance or adequate intake for the essential trace and ultratrace minerals II. Iron A. Sources 1. Iron is found in foods in two forms, one being heme and the other being nonheme. Heme iron is found in animal products. Nonheme iron is found in plant foods 2. Figures and Tables a. Figure 13.2 – heme iron, a metalloporphyrin b. Table 13.2 – iron content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Heme iron must be hydrolyzed from the globin portion of hemoglobin and myoglobin prior to absorption; this is accomplished by proteases in the stomach and small intestine 2. A heme carrier protein (hcp1) transports the heme across the brush border membrane; the iron is either used by the enterocyte, stored as ferritin, excreted, or transported out of enterocytes

3. Nonheme iron must be hydrolyzed through hydrochloric acid in the stomach and proteases in the stomach and small intestine 4. Iron is reduced by reductases and the divalent metal transporter carries the reduced iron across the brush border membrane into the enterocyte 5. Fe3+ attaches to transferrin for transport in the blood 6. Chelators may bind with nonheme iron and inhibit or enhance its absorption 7. Iron absorption is regulated by body iron and cellular iron 8. Transferrin binds and transports iron 9. Iron is stored in the liver, bone marrow, and spleen 10. Key Terms a. Chelators – small organic compounds that form a complex with another compound, such as a mineral 11. Figures and Tables a. Figure 13.3 – iron digestion, absorption, enterocyte use, and transport b. Figure 13.4 – overview of some pathways stimulating hepcidin synthesis c. Figure 13.5 – influence of intracellular iron on the translation of ferritin mRNA and transferrin receptor mRNA d. Figure 13.6 – overview of cellular iron uptake C. Functions and Mechanisms of Action 1. Iron functions in the body as part of several proteins, including enzymes for which it serves as a cofactor 2. Figures and Tables a. Table 13.3 – selected functions of iron b. Figure 13.7 – heme biosynthesis D. Turnover 1. Iron conservation and constant recycling is necessary to supply the body with enough iron 2. Iron that enters the plasma for distribution or redistribution by transferrin results from hemoglobin and ferritin degradation 3. Figures and Tables a. Figure 13.8 – internal iron exchange E. Interactions with Other Nutrients 1. Iron interacts with ascorbic acid, copper, zinc, vitamin A, and lead F. Excretion 1. Total daily losses for adult males are 0.9–1.2 mg/day, and 0.7–0.9 mg/day for females G. Recommended Dietary Allowance 1. Iron RDAs for adult men are 6 mg/day and 8 mg/day, and RDA for premenopausal women is 8.1 mg/day 2. During pregnancy, the RDA is 27 mg/day and during lactation it is 9 mg/day H. Deficiency 1. Iron deficiency is seen more in infants and young children, adolescents, females during childbearing years, and pregnant women © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Iron deficiency is associated with iron-deficiency anemia 3. Figures and Tables a. Figure 13.9 – sequential changes in iron status associated with iron depletion I. Toxicity 1. The Tolerable Upper Intake Level for iron for adults is 45 mg 2. Acute toxicity may lead to death, and the free radical manner of unbound iron may cause gastrointestinal damage 3. Chronic iron toxicity is generally associated with hemochromatosis, causing increased iron absorption J. Assessment of Nutriture 1. The most common index used to diagnose iron-deficiency anemia is hemoglobin III. Zinc A. Sources 1. Zinc is found in foods including red meats and seafood 2. Figures and Tables a. Table 13.4 – zinc content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Zinc needs to be hydrolyzed from amino acids and nucleic acids prior to absorption 2. Most zinc is absorbed via Zrt- and Irt-like protein 4 across the brush border membrane 3. Divalent mineral transporter 1 and amino acids may play a minor role in zinc absorption across the brush border membrane 4. Some zinc may be directed into the feces if bound to inhibitors 5. With high zinc intakes, zinc may be absorbed between cells; within cells, zinc may be used functionally or stored 6. Zinc may be transported across the basolateral membrane by ZnT1; zinc binds to proteins for transport in the blood 7. Figures and Tables a. Figure 13.10 – digestion, absorption, enterocyte use, and transport of zinc b. Figure 13.11 – binding of zinc by oxalic acid and phytic acid C. Functions and Mechanisms of Action 1. Zinc plays a vital role in facilitating hundreds of biochemical reactions, impacting most metabolic pathways and physiological processes in the body 2. Figures and Tables a. Table 13.5 – selected functions of zinc b. Figure 13.12 – partial structure of carboxypeptidase A c. Figure 13.13 – role of zinc in gene expression D. Interactions with Other Nutrients

1. Zinc and vitamin A interact, along with zinc and copper, zinc and calcium, and zinc and cadmium E. Excretion 1. Zinc is lost from the body primarily via the gastrointestinal tract, kidneys, and skin; most zinc is excreted through the feces F. Recommended Dietary Allowance 1. Daily requirements for zinc for adult men and women are set at 9.4 mg and 6.8 mg, respectively 2. The RDA for zinc during pregnancy is 11 mg/day and lactation is 12 mg/day G. Deficiency 1. Signs and symptoms of zinc deficiency are growth retardation, skeletal abnormalities, poor wound healing, diarrhea, skin rash/lesions/dermatitis, and delayed sexual maturation 2. In adults, symptoms include anorexia, diarrhea, lethargy, depression, skin rash/lesions/dermatitis, hypogeusia, alopecia, vision problems, and impaired immune function H. Toxicity 1. Acute zinc toxicity produces symptoms of metallic taste, headache, nausea, vomiting, epigastric pain, abdominal cramps, and bloody diarrhea 2. Chronic ingestion of zinc in amounts of 40 mg results in copper deficiency as well as neurological problems 3. The Tolerable Upper Intake Level for zinc is set at 40 mg daily I. Assessment of Nutriture 1. Zinc may be measured in red blood cell, leukocytes, neutrophils, and plasma or serum IV. Copper A. Sources 1. Richest sources of copper are meats and shellfish 2. Figures and Tables a. Table 13.6 – copper content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Copper is released from food and is reduced, most likely by cytochrome b ferric/cupric reductase 2. Reduced copper crosses the brush border membrane by a high-affinity Ctr1 transporter, and a lesser extent by DMT1 3. Within the cytosol, the copper binds to chaperones for transport and delivery to target enzymes 4. Copper is delivered to enzymes and is used by cells or binds to metallothionein for storage 5. ATP7A transports reduced copper across the basolateral membrane 6. Copper attaches to proteins for transport in the blood 7. Figures and Tables

a. Figure 13.14 – overview of copper digestion, absorption, enterocyte use, and transport C. Functions and Mechanisms of Action 1. Copper participates as an enzyme cofactor at either the active site or allosteric site of the enzyme 2. Figures and Tables a. Table 13.7 – selected functions of copper D. Interactions with Other Nutrients 1. Copper is known to react with iron and molybdenum E. Excretion 1. Copper is primarily excreted through the bile into the feces 2. Figures and Tables a. Figure 13.15 – role of ATP7B in copper use and excretion in the liver F. Recommended Dietary Allowance 1. The RDA for copper is set at 900 µg/day, 1,000 µg/day for pregnancy, and 1,300 µg/day for lactation G. Deficiency 1. Most common copper deficiency symptoms include hypochromic and microcytic anemia 2. Other manifestations include hypopigmentation, impaired immune function, blood vessel/connective tissue and bone abnormalities, altered cholesterol metabolism, hypotonia, and cardiovascular and pulmonary dysfunction H. Toxicity 1. Copper toxicity is rare in the United States. The Tolerable Upper Intake Level is set at 10 mg/day by the Food and Nutrition Board 2. Copper toxicity symptoms include nausea, vomiting, diarrhea, weakness, lethargy, anorexia, hematuria, liver damage, and kidney damage 3. Wilson’s disease is a genetic disorder resulting in a mutation in the gene coding for ATP7B, which is characterized by copper toxicity and lethal if not treated I. Assessment of Nutriture 1. Copper may be assessed via serum, plasma, or red blood cells V. Selenium A. Sources 1. The richest sources of selenium include organ meats and seafood, followed in descending order by muscle meats, cereals and grains, eggs, and dairy products 2. Figures and Tables a. Table 13.8 – selenium content of selected foods b. Figure 13.16 – selenomethionine and selenocysteine B. Digestion, Absorption, Transport, and Storage 1. Selenium is absorbed through the small ingestion and doesn’t require digestion prior to absorption into enterocytes © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

2. Selenoamino acids are transported across the basolateral membrane using amino acid transporters; however, the mechanisms by which inorganic selenium crosses the enterocyte’s basolateral membrane to enter the portal blood are unknown 3. In the liver, organic and inorganic forms of selenium are metabolized; it is stored in the kidneys, liver, and spleen, with lower amounts stored in the pancreas, heart, brain, and lungs C. Metabolism 1. Selenium is metabolized in the liver 2. Synthesis of selenocysteine-containing proteins begins with selenophosphate and the amino acid serine\ 3. Selenocysteine synthase replaces the hydroxyl group of serine with a HSe from selenophosphate to form SEC-tRNASEC 4. SEC-tRNA delivers selenocysteine to the growing peptide chains of the various SEC-containing proteins like glutathione peroxidase, iodothyronine 5′-deiodinase, and thioredoxin reductase, among others 5. Figures and Tables a. Figure 13.17 – selenium metabolism in the liver D. Functions and Mechanisms of Action 1. Selenium roles are related to its function as an integral part of specific proteins/enzymes in the body; these proteins primarily function in antioxidant capacities, and thus regulate cell redox status 2. Figures and Tables a. Table 13.9 – proposed functions/characteristics of selected selenoproteins E. Interactions with Other Nutrients 1. Selenium may help prevent some toxic effects associated with some metals F. Excretion 1. Urinary excretion of selenium enables body selenium homeostasis G. Recommended Dietary Allowance 1. RDA for selenium for adults is 55 µg/day, 60 µg/day during pregnancy, and 70 µg/day during lactation H. Deficiency 1. Selenium deficiency occurs in regions such as China, central Africa, and parts of Europe; the deficiency is linked to Keshan disease and KashinBeck disease 2. Keshan disease is characterized by cardiomyopathy involving cardiogenic shock, congestive heart failure, or both, along with multifocal necrosis of heart tissue 3. Kashin-Beck disease is characterized by osteoarthropathy involving chronic degeneration and necrosis of the joints and the epiphyseal-plate cartilages of the legs and arms 4. Total parenteral nutrition has risks of selenium deficiency; selenium deficiency symptoms include poor growth, muscle pain and weakness, loss

of pigmentation of hair and skin, whitening of nail beds, and reduced immune system function I. Toxicity 1. Selenium toxicity, selenosis, has been observed in miners and people who consume excessive amounts 2. Symptoms of toxicity include nausea, vomiting, fatigue, diarrhea, hair brittleness, brittle and thickened nails, muscle cramps, paresthesia, interference in sulfur metabolism, and inhibition of protein synthesis J. Assessment of Nutriture 1. Serum or plasma selenium concentrations are widely used for assessment VI. Chromium A. Sources 1. Good dietary sources of chromium are generally thought to include meats and grains along with some vegetables and fruits B. Digestion, Absorption, Transport, and Storage 1. Chromium may be released from food components in acidic solutions with chromium being absorbed throughout the small intestine, especially the jejunum; it is thought to be absorbed via passive diffusion 2. Chromium binds to transferrin for transport in the blood; if transferrin sites are unavailable, then albumin may transport it 3. The body contains 4–6 mg of chromium between the liver, spleen, bone, kidneys, heart, and pancreas C. Functions and Mechanisms of Action 1. Chromium is thought to potentiate the action of insulin 2. Key Terms a. Glucose tolerance factor – chromium-containing compound whose structure has yet to be characterized but may potentiate the action of insulin in the body 3. Figures and Tables a. Figure 13.18 – proposed role of chromium as part of chromodulin in potentiating insulin’s reactions D. Excretion 1. Most chromium is excreted from the body via urine E. Adequate Intake 1. Adequate Intakes for chromium for adult men through 50 years of age is 35 µg and 25 µg for adult women 2. Values drop to 30 µg and 20 µg for men and women over 50 years of age, respectively; pregnancy AI is 30 µg and lactation AI is 45 µg F. Deficiency 1. Chromium deficiency symptoms include weight loss, peripheral neuropathy, elevated plasma glucose concentrations or impaired glucose use, and high plasma free fatty acid concentrations G. Toxicity

1. The use of chromium picolinate has been associated with chromosomal and organ damage 2. Oral supplementation of 1,000 µg of chromium appears to be safe H. Assessment of Nutriture 1. No specific tests are available to determine chromium status VII. Iodine A. Sources 1. Good sources for iodine include seafood, meats, eggs, and dairy 2. Figures and Tables a. Table 13.10 – iodine content of selected foods B. Digestion, Absorption, Transport, and Storage 1. Dietary iodine is either bound to amino acids or found free 2. Organic bound iodine is released during digestion and converted to iodide 3. Iodide is absorbed rapidly, mostly from the stomach and some in the duodenum; following absorption, free iodide appears in the blood 4. The thyroid gland traps iodide most aggressively through active transport 5. Iodide uptake also occurs in salivary glands C. Functions and Mechanisms of Action 1. The main function of iodide is in the synthesis of the thyroid hormones, thyroxine and triiodothyronine 2. Figures and Tables a. Figure 13.19 – overview of iodine intrathyroidal metabolism and hormonogenesis b. Table 13.11 – selected physiological effects of thyroid hormones D. Interactions with Other Nutrients 1. Iodine interacts with selenium, iron, vitamin A, and goitrogens 2. Figures and Tables a. Figure 13.20 – goitrin E. Excretion 1. The kidneys have no mechanism to conserve iodide and therefore provide the major route for iodide excretion F. Recommended Dietary Allowance 1. The RDA for iodine for adults is 150 µg/day, 220 µg/day during pregnancy, and 290 µg/day during lactation G. Deficiency 1. Iodide uptake affects the thyroid-stimulating hormone. Iodine deficiency symptoms include goiter, thyroid dysfunction, growth, and neurological cretinism H. Toxicity 1. The Tolerable Upper Intake Level for iodine has been set at 1,100 µg/day. Signs of acute iodide toxicity include burning of the mouth, throat, and stomach; nausea; vomiting; diarrhea; and fever I. Assessment of Nutriture 1. Iodine may be measured via urinary excretion © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

VIII. Manganese A. Sources 1. Whole-grain cereals, nuts, and leafy vegetables are considered manganeserich foods B. Digestion, Absorption, Transport, and Storage 1. It is unclear if manganese bound to food needs to undergo digestion prior to absorption; manganese is absorbed via an active carrier protein such as divalent mineral transport 1 and/or Zrt- and Irt-like protein 14. Diffusion may contribute to absorption at higher manganese intakes 2. Manganese entering into portal circulation from the gastrointestinal tract may either remain free or become bound to α-2-macroglobulin before traversing the liver 3. Upon release from the liver, some manganese may remain free in the blood and some bound to albumin, α-2-macroglobulin, β-globulin, or γ-globulin, or be oxidized and complexed with transferrin 4. Manganese is cleared quickly from the blood; manganese is found in most tissues, highest being in the bones, liver, pancreas, and kidneys C. Functions and Mechanisms of Action 1. Manganese functions both as an enzyme activator and as a constituent of metalloenzymes D. Interactions with Other Nutrients 1. Manganese reacts with iron, calcium, zinc, and possibly some trace elements E. Excretion 1. Manganese is excreted primarily via the bile in the feces F. Adequate Intake 1. RDA for manganese for adult men is 2.3 mg/day and 1.8 mg/day for adult female, 2 mg/day during pregnancy, and 2.6 mg/day during lactation G. Deficiency 1. Manganese deficiency is rare and symptoms include nausea; vomiting; dermatitis; decreased serum manganese; decreased fecal manganese excretion; increased serum calcium, phosphorus, and alkaline phosphatase; decreased growth of hair and nails, changes in hair and beard color; poor bone formation and skeletal defects; decreased clotting proteins; and altered carbohydrate and lipid metabolism H. Toxicity 1. The Tolerable Upper Intake Level for manganese is 11 mg/day. Toxicity symptoms include cough, bronchitis, pneumonitis, reduced lung function, tremors, diminished memory capacity, loss of coordination, insomnia, headache, forgetfulness, anxiety, mood changes, compulsive behaviors, reduced reaction time, rapid hand movements, and gait disturbance I. Assessment of Nutriture 1. Manganese concentrations may be measured in the plasma/serum and whole blood © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

IX. Molybdenum A. Sources 1. Widespread among foods with better dietary sources being legumes, meat, fish, and poultry B. Digestion, Absorption, Transport, and Storage 1. Molybdenum doesn’t appear to require digestion prior to absorption from the small intestine, especially the proximal region; absorption is thought to be passive 2. Molybdenum is found in the liver, kidneys, and bone in highest concentrations C. Functions and Mechanisms of Action 1. The biochemical role of molybdenum centers around the redox function of the element and its necessity as a cofactor in the form of molybdopterin for four metalloenzymes, all of which catalyze oxidation-reduction reactions 2. Figures and Tables a. Figure 13.21 – molybdopterin structures b. Figure 13.22 – molybdenum’s role in hypoxanthine and xanthine degradation c. Figure 13.23 – reduction of N-hydroxylated compounds such as benzamidoxine by the molybdenum-dependent enzyme amidoxime reductase D. Interactions with Other Nutrients 1. The most notable interaction is molybdenum with copper E. Excretion 1. Most molybdenum is excreted as molybdate in the urine

F. Recommended Dietary Allowance 1. RDA for molybdenum for adults is 45 µg/day, and 50 µg/day during pregnancy and lactation G. Deficiency 1. Molybdenum deficiency is rare and associated with high blood concentrations of methionine, hypoxanthine, and xanthine, as well as low blood concentrations of uric acid 2. Genetic defects in enzymes involved in molybdopterin synthesis disrupt both cofactor production and molybdenum use in molybdenum-dependent enzymes 3. Deficiency is characterized by poor feeding, attenuated brain growth, seizures, severe neurological damage, and death in childhood H. Toxicity 1. Molybdenum appears to be relatively nontoxic with symptoms such as gout. The Tolerable Upper Intake Level for molybdenum has been set at 2 mg I. Assessment of Nutriture 1. Molybdenum appears to distribute itself fairly equally between the plasma and red blood cells, but no indicator has been established

Resources Suggested Readings • Collins JF, Prohaska JR, Knutson MD. Metabolic crossroads of iron and copper. Nutr Rev. 2010; 68:133–47. • Gammella E, Buratti P, Cairo G, Recalcati S. Macrophages: central regulators of iron balance. Metallomics. 2014; 6:1336–45. • Piperno A, Mariani R, Thrombini P, Girelli P. Hepcidin modulation in human diseases: from research to clinic. World J Gastroenterol. 2009; 15:538–51. • Cousins RJ. Gastrointestinal factors influencing zinc absorption and homeostasis. Int J Vitam Nutr Res. 2010; 80:243–8. • Klug A. The discovery of zinc fingers and their development for practical applications in gene regulation and genome manipulation. Quart Rev Biophys. 2010; 43:1–21. • Toth K. Zinc in neutrotransmission. Ann Rev Nutr. 2011; 31:139–53. • Wang X, Zhou B. Dietary zinc absorption: a play of Zips and ZnTs in the gut. Life 2010; 62:176–82. • Scheiber IF, Mercer JFB, Dringen R. Metabolism and functions of copper in brain. Prog Neurobiol. 2014; 116:33–57. • Tumer Z, Moller LB. Menkes disease. Eur J Hum Genetics. 2010; 18:511–8. • Wu F, Wang J, Pu C, Qiao L, Jiang C. Wilson’s disease: a comprehensive review of the molecular mechanisms. Int J Mol Sci. 2015; 16:6419–31. • National Institutes of Health, Office of Dietary Supplements. Selenium Dietary Supplement Fact Sheet – Health Professional. • Pillai R, Uyehara-Lock JH, Bellinger FP. Selenium and selenoprotein function in brain disorders. IUBMB Life. 2014; 66:229–39. • National Institutes of Health, Office of Dietary Supplements. Chromium Dietary Supplement Fact Sheet – Health Professional. © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

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Molecular and Cellular Endocrinology 2010, volume 322, is devoted to disorders involving iodine utilization. Roth JA. Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination. Biol Res. 2006; 39:45–57. Mendel RR. The molybdenum cofactor. J Biol Chem. 2013; 288:13165–72.

Additional Resource • Koo, B. B., Bagai, K., & Walters, A. S. (2016). Restless legs syndrome: current concepts about disease pathophysiology. Tremor and Other Hyperkinetic Movements, 6, 401. Article ID Restless legs syndrome: current concepts about disease pathophysiology]

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

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What are the selected physiological roles of the essential trace and ultratrace minerals? • Chromium – possibly potentiates insulin signaling • Copper – iron use; synthesis of collagen, pigment, neurotransmitters • Iodine – thyroid hormone synthesis • Iron – oxygen transport and use; amino acid metabolism; antioxidant; carnitine, collagen, and thyroid hormone synthesis • Manganese – brain and CNS function, collagen, bone, growth, urea synthesis, glucose and lipid metabolism • Molybdenum – metabolism of purines, pyrimidines, pteridines, aldehydes, oxidation • Selenium – protection against hydrogen peroxide and free radicals, thyroid hormone production • Zinc – nutrient metabolism, collagen formation, alcohol detoxification, carbon dioxide elimination, sexual maturation, cell replication and growth What are the approximate body content for each of the minerals above? • Chromium – 4–6 mg • Copper – 50–150 mg • Iodine – 15–20 mg • Iron – 2–4 g • Manganese – 10–20 mg • Molybdenum – 2 mg • Selenium – 20 mg • Zinc – 1.5–3.0 g

Assignment – Individual Paper •

Superoxide dismutase is a necessary antioxidant. Describe the roles of superoxide dismutase and what would happen if superoxide dismutase is not functioning. o Superoxide dismutase is an antioxidant that is a copper- and zincdependent enzyme. The antioxidant catalyzes the removal of the superoxide radicals. Superoxide dismutase reduces reactive oxygen and hydrogen to hydrogen peroxide. It serves a protective role.

Answer Keys Worksheet 1: Responding to Research– Iron and Restless Leg Syndrome 1. a 2. c 3. decreased 4. No, there are also deficiencies in the ability for the body to digest, absorb, transport, metabolize, and store iron. Worksheet 2: Nutrition Lab – ATP7B in Copper Use 1. Ctr1 transports copper into the hepatocytes from the blood. 2. Atox1 functions as a chaperone to take Cu1+ to the trans-Golgi network. 3. Within the trans-Golgi network (TGN), copper is incorporated into ceruloplasmin (Cp) and other cuproenzymes. ATP7B transports the proteins into the secretory pathway. 4. In the presence of excess copper, ATP7B moves from the TGN to copper-containing cytosolic vesicles (and lysosomes—not shown) to direct the secretion of the copper from these sites into the bile duct.

Worksheet 1: Research Study – Iron and Restless Leg Syndrome Iron is necessary in our diets for our body to function. One of the main functions is oxygen transport. However, iron plays other roles, one which most wouldn’t even think of is restless leg syndrome. Read the following article and then respond to the questions. • Koo, B. B., Bagai, K., & Walters, A. S. (2016). Restless legs syndrome: current concepts about disease pathophysiology. Tremor and Other Hyperkinetic Movements, 6, 401. Article ID Restless legs syndrome: current concepts about disease pathophysiology] 1. Iron deficiency has shown to cause restless leg syndrome. a. True b. False __________ 2. Cindy is very frustrated with her restless leg syndrome. She has been having episodes more than five times a month. She wants screening done to test what is causing her symptoms and to see if there is anything that can be done. Which biological systems should be analyzed for her symptoms? a. Serotonergic system, oxygen-sensing system, and skeletal system. b. Serotonergic system, skeletal system, and dopaminergic system. c. Serotonergic system, dopaminergic system, and glutamatergic system. d. Skeletal system, dopaminergic system, and glutamatergic system. __________ 3. Iron effects on restless leg syndrome have shown that the iron level is __________ compared to those who don’t suffer from restless leg syndrome. a. decreased b. increased c. the same __________ 4. Is the link between restless leg syndrome and iron deficiency only due to decreased intake of iron?

Worksheet 2: Nutrition Lab – ATP7B in Copper Use Using Figure 13.15, describe steps one through four.

Instructor’s Manual Advanced Nutrition and Human Metabolism, Gropper, 7e Chapter 14 – Nonessential Trace and Ultratrace Minerals Table of Contents • • • • •

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Chapter Outline Resources Perspectives – Classroom Discussion Assignment – Individual Paper Answer Keys o Case Study o Responding to Research o Nutrition Lab Worksheet 1: Responding to Research – Drinking Water Worksheet 2: Nutrition Lab – Nonessential Minerals

Chapter Outline I. Introduction 1. Trace elements are minerals that are needed in amounts less than 100 mg/day, while ultratrace elements are those with a required amount less than 1 mg/day 2. There are at least 18 elements classified as ultratrace 3. Figures and Tables a. Figure 14.1 – periodic table highlighting important nonessential trace and ultratrace elements b. Table 14.1 – nonessential trace and ultratrace elements II. Fluoride 1. Typically found in metal, nonmetal, or organic compound. Not considered an essential nutrient A. Sources 1. Community drinking water has been fluoridated since about 1945 in the United States; also found in some grains and cereal products, fish, and tea 2. Figures and Tables a. Table 14.2 – fluoride content of selected food groups B. Absorption, Transport, Storage, and Excretion 1. In foods, fluoride may be bound to proteins and must be hydrolyzed 2. Fluoride is transported in the blood free as ionic fluoride and hydrofluoric acid, as well as bound to plasma proteins 3. Ionic fluoride is rapidly excreted in the urine C. Functions and Deficiency 1. Fluoride replaces some of the hydroxide ions in hydroxyapatite to form fluorohydroxyapatite, which increases the mineralization of the crystalline © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

structure and is less acid-soluble than hydroxyapatite; this increases the resistance of tooth enamel to acid demineralization D. Recommended Intake, Toxicity, and Assessment of Nutriture 1. Adequate Intake for adult males is 4 mg/day and for adult females is 3 mg/day 2. Acute toxicity manifests as nausea, vomiting, diarrhea, acidosis, and cardiac arrhythmias 3. Death has been reported at an ingestion of 5–10 g of sodium fluoride 4. Chronic fluoride toxicity is characterized by changes in the teeth, skeleton, and nonskeletal tissues III. Arsenic 1. Colorless and odorless, and essentiality is not certain A. Sources 1. Arsenic is present in water, rocks, and soils. Seafood is a rich source of arsenic 2. Figures and Tables a. Figure 14.2 – two forms of arsenic commonly found in seafoods B. Absorption, Transport, Storage, and Excretion 1. Small amounts of arsenic from the environment may be absorbed through inhalation and via the skin, while 90% or more of arsenate and arsenite is absorbed in the small intestine from water 2. In the liver, organic forms arsenobetaine and arsenocholine undergo little metabolism; inorganic arsenic is extensively metabolized 3. Arsenic may conjugate with glutathione; it is excreted rapidly by the kidneys 4. Figures and Tables a. Figure 14.3 – metabolism of arsenic C. Functions and Deficiency 1. No biological function for arsenic has been demonstrated in humans D. Recommended Intake, Toxicity, and Assessment of Nutriture 1. No recommended intake amount for arsenic has been established. Acute toxicity results in abdominal pain, vomiting, diarrhea, muscle cramping, numbness and tingling, and liver damage 2. Chronic toxicity affects most body systems IV. Boron 1. Boron is a beneficial bioactive element for humans, but not considered essential A. Sources 1. Boron food sources are fruits, vegetables, nuts, and legumes B. Absorption, Transport, Storage, and Excretion 1. Greater than 85% of ingested boron is absorbed as boric acid by passive diffusion in the gastrointestinal tract; also found in the blood, with uptake occurring in bones, nails, and hair © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

C. Functions and Deficiency 1. Boron has beneficial effects on bone, immune, and brain function D. Recommended Intake, Toxicity, and Assessment of Nutriture 1. Recommended intakes have not been established for boron. Intakes of 1–3 mg/day have been beneficial for brain and bone health 2. Acute boron toxicity results in nausea, vomiting, diarrhea, dermatitis, and lethargy 3. Chronic boron toxicity is associated with nausea, poor appetite, anemia, dermatitis, and seizures V. Nickel 1. Nickel is considered as possibly essential, but no role for nickel has been established A. Sources 1. Nickel is found higher in plant sources B. Absorption, Transport, Storage, and Excretion 1. Nickel absorption from food is low, less than 10%; absorption of nickel is higher from water and beverages 2. Nickel is absorbed across the enterocyte’s brush border membrane and likely competes with iron for carrier transport 3. In the blood, nickel binds to albumin, peptides, and amino acids 4. Most nickel is excreted in the urine C. Functions and Deficiency 1. No specific role for nickel in humans has been identified D. Recommended Intake, Toxicity, and Assessment of Nutriture 1. The Tolerable Upper Intake Level for nickel for adults is 1.0 mg/day in the form of soluble nickel salts 2. Acute nickel toxicity symptoms include headache, nausea, vomiting, insomnia, and irritability VI. Silicon 1. Silicon has not been found to be essential and no specific biochemical function for silicon has been established A. Sources 1. Plant foods contain silicon B. Absorption, Transport, Storage, and Excretion 1. Silicon is found in water as monosilicic acid, which is readily absorbed from the proximal small intestine 2. Silicon in plant foods contains phytolithic silica that requires digestion 3. Once absorbed into the blood, it is taken up by the liver, lungs, skin, bones, heart, muscles, spleen, and testes 4. Silicon is excreted via the urine C. Functions and Deficiency 1. Silicon is thought to play both metabolic and structural/binding roles in connective tissues © 2018 Cengage Learning. All Rights Reserved. May not be scanned, copied or duplicated, or posted to a publicly accessible website, in whole or in part.

D. Recommended Intake, Toxicity, and Assessment of Nutriture 1. No Tolerable Upper Intake Level for silicon; a safe upper level of 700 mg/day has been suggested VII.

Vanadium 1. Occurs in several oxidation states A. Sources 1. The richest sources of vanadium are fish and shellfish B. Absorption, Transport, Storage, and Excretion 1. Metabolism and absorption of vanadium vary with its oxidation states 2. Vanadate may be absorbed directly via the same transport carrier system as used by phosphate and then reduced intracellularly by glutathione 3. The total pool of vanadium is about 100–200 µg 4. Renal excretion is the major route for elimination of absorbed vanadium C. Functions and Deficiency 1. No specific biochemical function has been identified for vanadium, but may have roles with enzymes, phosphates, insulin, and carcinogenic properties D. Recommended Intake, Toxicity, and Assessment of Nutriture 1. Human requirement for vanadium is not established 2. A Tolerable Upper Intake Level is set at 1.8 mg/day, and daily intakes of up to 100 µg are considered safe 3. Mild toxic manifestations include green tongue syndrome, diarrhea, and abdominal cramps 4. Chronic toxicity manifests as hypertension, neurological disorders, respiratory tract irritation, hepatic damage, cardiac damage, and renal damage

VIII.

Cobalt 1. Little evidence exists that cobalt plays a role in human nutrition other than being part of vitamin B12

Resources Suggested Readings • Centers for Disease Control and Prevention. Statement on the evidence supporting the safety and effectiveness of community water fluoridation. www.cdc.gov/fluoridation/pdf/statement-cwf.pdf. Accessed May 1, 2015. • Gazzano E, Bergandi L, Riganti C, et al. Fluoride effects: the two faces of Janus. Curr Med Chem. 2010; 17:2431–41. • Jha SK, Mishra VK, Sharma DK, Damodaran T. Fluoride in the environment and its metabolism in humans. Rev Environ Contam Tox. 2011; 211:121–42. • Hunt CD. Dietary boron: progress in establishing essential roles in human physiology. J Trace Elem Med Biol. 2012; 26:157–60. • Willsky GR, Halvorsen K, Godzala ME, Chi L, Most MJ, Kaszynski P, Crans DC, Goldfine AB, Kostyniak PJ. Coordination chemistry may explain pharmacokinetics

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and clinical response of vanadyl sulfate in type 2 diabetic patients. Metallomics 2013; 5:1491–1502. Eckhert CD. Trace Elements. In: Modern Nutrition in Health and Disease, 11th ed. Baltimore, MD: Lippincott Williams & Wilkins. 2014, pp. 256–7.

Additional Resource • Stein, R. (2015). Feds say it’s time to cut back on fluoride in drinking water. National Public Radio, Public Health, All Things Considered. Feds say it’s time to cut back on fluoride in drinking water

Perspectives – Classroom Discussion You may pose these questions to your students when discussing the perspectives section of this chapter. •

What are the nonessential trace and ultratrace minerals and their possible physiological roles?

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What are those minerals potential deficiency symptoms in animals? • Fluoride – growth and fertility • Arsenic – impaired growth and reproduction • Boron – impaired bone health, cognitive/brain function, and immune response • Nickel – depressed reproduction and growth, and impaired hematopoiesis • Silicon – decreased collagen, and long bone and skull abnormalities • Vanadium – impaired fertility, reduced survival, growth, and development

Assignment – Individual Paper •

Arsenic is usually thought of in a negative tense. However, the nutrient appears to be bioactive. Even though the essentiality of arsenic is lacking, discuss the need for arsenic, sources of arsenic, and possible toxicities of arsenic.

Sources of arsenic include water and seafood. There is no biological function for arsenic and no recommended intake amount, but there are toxicity risks of arsenic. Acute toxicity results in abdominal pain, vomiting, diarrhea, muscle cramping, numbness and tingling, and liver damage. Chronic toxicity affects most body systems

Answer Keys Research Study – Drinking Water 1. b 2. d 3. fluorosis 4. Too much fluoride may lead to increased risks of thyroid problems, attention deficit disorders, and lower IQs. Nutrition Lab – Nonessential Minerals 1. It is vital to learn about the nonessential trace and ultratrace minerals, so you are aware of their bioactivity, recommended daily intakes, and toxicities 2. Fluoride – fish, legumes, grains, tea, drinking water Arsenic – seafood, meat, grains, grain products, water Boron – fruits, vegetables, legumes, nuts Nickel – nuts, legumes, grains, cocoa products Silicon – beer, whole grains, lentils, root vegetables Vanadium – fish, shellfish, grains, black pepper, parsley, mushroom, dill seed 3. Acute toxicity for fluoride manifests as nausea, vomiting, diarrhea, acidosis, and cardiac arrhythmias. Death has been reported at an ingestion of 5–10 g of sodium fluoride. Chronic fluoride toxicity is characterized by changes in the teeth, skeleton, and nonskeletal tissues 4. No, nonessential minerals should not be completely avoided because although they are nonessential, they do have bioactivitiy.

Worksheet 1: Responding to Research – Drinking Water Fluoride was added to the drinking water in the United States to help combat tooth decay. However, now many questions have arisen as to whether or not it is necessary any longer in the drinking water. There are risks to consuming too much fluoride in the daily diet, but are those risks enough to eliminate it from the drinking water? Read the following article and then respond to the questions. • Stein, R. (2015). Feds say it’s time to cut back on fluoride in drinking water. National Public Radio, Public Health, All Things Considered. Feds say it’s time to cut back on fluoride in drinking water 1. All drinking water in the United States contains fluoride. a. True b. False __________ 2. Nate is 5 now and is going in for his first dental visit. He has always grown up on the family farm, eating foods grown and raised on the farm. The farm has a water system that collects rain water that they use for drinking. Nate’s dentist is concerned because Nate has decaying baby teeth. Why? a. Nate’s diet does not contain enough variety. b. Baby teeth decay when they are close to being replaced by adult teeth. c. Nate consumes too much fluoride. d. Nate consumes too little fluoride. __________ 3. The effects of too much fluoride are __________ of the teeth. a. decaying b. fluorosis c. whitening __________ 4. What are the other risks of too much fluoride consumption, which you learned in this article?

Worksheet 2: Nutrition Lab – Nonessential Minerals 1. Why is it important to learn about the nonessential trace and ultratrace minerals?

2. What are the food sources for each of the six nonessential minerals discussed in this chapter?

3. What are the toxicities for fluoride?

4. Should nonessential minerals be completely avoided? Why or why not?