Lesson 19

Lesson 19. Cholesterol and Lipoproteins I 1. a. b. c. d.

What is incorrect about the structure of cholesterol?

Steroid with four hydrocarbon rings (3 w/ 6C + 1 w/ 5C) Amphipathic (hydroxyl group near polar heads + most of molecule near fatty acid chains) Single polar hydroxyl group No double bond or hydrocarbon tail

1. A: Cholesterol has a hydrocarbon tail, single polar OH, methyl group, and double bond. It is a steroid w/ 4 rings and the OH makes it amphipathic.

2. Where is cholesterol biosynthesis least likely to occur? a. Liver b. Intestine c. Adrenal cortex d. Reproductive tissue e. Adrenal medulla 2. E: The largest production of cholesterol is in the liver, intestine, adrenal cortex, and reproductive tissue.

3. What is true about cholesterol biosynthesis? a. Some carbons are derived from acetyl-CoA b. NADPH is the reducing agent c. Hydrolysis of acetyl CoA and GTP drives the endergonic process d. Synthesis begins in the ER and finishes in the cytosol 3. B: NADPH not NADH is the reducing agent. All carbons are derived from acteyl-CoA. Hydrolysis of acetyl CoA and ATP (not GTP) drives the endergonic (not exergonic) process.

Synthesis begins in the cytoplasm and ends in the ER. 4. Place the 6 molecules of cholesterol biosynthesis in order: I. Acetyl CoA II. Mevalonate III. Squalene IV. Isopentenyl pyrophosphate (IPP) V. Lanosterol VI. Cholesterol a.I, II, III, IV, V, VI b.I, II, IV, III, V, VI c. I, II, III, V, IV, VI d. I, II, IV, V, III, VI 4. B: Cytoplasm: Acetyl CoA -> Mevalonate -> IPP ER: IPP -> Squalene -> Lanosterol -> Cholesterol

5. In the Acetyl CoA to mevalonate reaction (#1 of 5 in cytoplasm): 2 acetyl CoA (C2) —condense—> acetoacetyl CoA (C4) 3rd acetyl CoA (C2) —HMG CoA synthase—> HMG CoA (C6) HMG CoA (C6) + 2NADPH —HMG CoA reductase—> Mevalonate (C6) What is true about the reduction of HMG CoA to mevalonate? a. Irreversible b. Targeted reaction enzyme for statins c. Releases 2 NADP + CoA d. All of the above 5. D: All are true!

6. In the mevalonate to IPP reaction (#2 of 5 in cytoplasm): Mevalonate (C6) —3 phosphorylations + decarboxylation—> Isopentyl pyrophosphate (IPP;C5) What is true regarding the reaction? a. Requires 3 ATP b. Releases CO2 and 1 phosphate c. IPP is an activated isoprene with 2 phosphates d. All of the above 6. Again, all of the above. 1 phosphate is released with CO2 at end so only 2 “pyro” phosphate on IPP. Requires 3 ATP since 3 phosphates used overall.

7. In the IPP to squalene reaction (#3 of 5 in ER): IPP (C5) —isomerize—> DMAPP (C5) + DMAPP —condense—> GPP (C10) + IPP (C5) —condense-> FPP (C15) + FPP (C15) —reduction—> Squalene (C30) What is true regarding the reaction? a. Requires 6 IPP and 18 ATP b. Uses NADH c. Uses NADP d. Releases CO2 7. A: I Detect Grassy Fawn Squares (5;5;10;15;30C). NADP+ is releases and NADPH is uses.

Pyrophosphate is releases in 2 transferase reactions and 2 PP are releases in condemnation of 2 FPP to make 1 Squalene.

8. In the Squalene to lanosterol (#4 of 5 in ER): Squalene (C30) —Squalene epoxide—> Cholesterol (C27) What is true regarding the reaction? a. Removal of 3 methyl groups b. Reduction + movement of double bond c. Requires OXYGEN and NADPH d. All of the above 8. D: All of the above are true

9. What occurs in the SREBP-SCAP complex for up regulation or down regulation of cholesterol synthesis?

I. Upregulation (low cholesterol): Transport proteins interact with SCAP to move from the ER to the Golgi II. Upregulation (low cholesterol): SREBP gets cleaved and the DNA-binding domain binds nucleus SER to enhance transcription of HMG CoA reductase III. Down regulation (high cholesterol): Cholesterol interact with SCAP to interact with Insig membrane protein so SREBP-SCAP stays in ER a. I b. I & III c. I, II, & III d. Both are incorrect 9. C: Upregulation (low cholesterol): Transport proteins interact with SCAP to move from the ER to the Golgi; SREBP gets cleaved and the DNA-binding domain binds nucleus SER to enhance transcription. Down regulation (high cholesterol): Cholesterol interact with SCAP to interact with Insig membrane protein so SREBP-SCAP stays in ER 10. What are the methods in which the amount and activity of HMG CoA reductase can be controlled?

I. SREBP-SCAP increase gene expression of enzyme via SCAP movement, SREBP cleavage to SER, decrease gene expression via SCAP-Insig II. Hormonal regulation increase gene expression via insulin/thyroxine and decrease expression via glucagon/glucocorticoids III. Ubiquitination and proteasomal degradation of enzyme-Insig complex during high cholesterol IV. Reversible, competitive inhibition of HMG-CoA reductase via statins that lower plasma cholesterol levels V. Dephosphorylation by phosphoprotein phosphatase (PPP) ACTIVES enzyme and Phosphorylation AMP-Kinase INACTIVATES enzyme a. I & II b. I, II, & III c. I, II, III, IV d. I, II, III, IV, & V 10. D: SREBP-SCAP (SCAP/SREBP-SER vs Insig) + Hormones regulate gene expression (thyroxine/insulin vs glucagon/glucocorticoids). Insig regulates enzyme degradation. Statins lower plasma cholesterol. PPP actives enzyme via dephosphyrlation and AMP-Kinase inactivates enzyme.

11. Statins lower intracellular cholesterol by inhibiting HMG-CoA reductase. Lower intracellular cholesterol levels increases the number of LDL receptors on the cell. More of these receptors means more uptake of extracellular LDL. What does this lead to? a. Increased plasma LDL b. Increases plasma cholesterol c. Decreased cellular cholesterol d. Decreases plasma cholesterol 11. D: More uptake of extracellular LDL into the cell means less is floating around in the blood.

12. Cholesterol cannot be converted into CO2 and H2O due to the ring structure. Instead, it is eliminated by conversion into bile acid/bile salts OR solubilization into bile for intestinal elimination. How are the 24 carbon bile acids made? a. Cholesterol -> Add a few OH groups -> Remove 3C -> Form a carboxyl -> Make Cholic acid or Chenodeoxycholic acid b. Cholesterol -> Remove a few OH groups -> Remove 4C -> Make Cholic acid or Chenodeoxycholic acid c. Cholesterol -> Remove a few OH groups -> Remove 3C -> Make Cholic acid or Chenodeoxycholic acid d. Cholesterol -> Remove 4C -> Make Cholic acid or Chenodeoxycholic acid 12. Cholesterol -> Add a few OH groups -> Remove 3C -> Make Cholic acid (triol) or Chenodeoxycholic acid (diol) 13. What is true about bile salts? a. Formed by adding a glycine or taurine to the carboxyl group of a bile acid (glycine is 3 times more common that taurine) b. Can be glycocholic acid or taurochenodeoxycholic c. Produced in liver and only secreted in salt form w/ phosphatidylcholine + soluble cholesterol d. Bile salts are negatively charged and act as effective detergents (more so than bile acids) e. All of the above.

13. E: All of the above 14. What is the correct order of the enterohepatic circulation?

I. Secretion of bile salts into bile at rate of 15-30g/day II. Return as a mix of bile salts AND acids to liver (only 3% lost, 97% reused so liver makes .5g/ day) III. Passage through the bile duct into the duodenum IV. Conversion of bile salts into bile acids via bacteria V. Uptake in ileum into the portal blood a. I, II, III, IV, V b. I, III, IV, V, II c. I, III, V, IV, II d. I, II, III, V, IV 14. B: Secrete -> Bile Duct into duodenum -> Convert bile salt to acid via bacteria -> Uptake in ileum -> 97% returned to liver which makes the remainder 3% or .5g/day that was lost 15. Cholestyramin or colestipol (resins) are non absorbable resins that bind bile acids to make them be excreted instead of reabsorbed. As a result this: a. More cholesterol is converted to bile acid (reduce plasma cholesterol) b. LDL receptors increase to improve cholesterol uptake c. The inhibitory mechanism acting on bile acid synthesis is inhibited d. All of the above 15. D: Resins effectively lower plasma cholesterol by increasing cholesterol conversion to bile acids

16. What is the correct association for each lipoprotein/glycoprotein? a. HDL; apoACE b. Chylomicrons; apoB-48, apoC, apoE c. VLDL; apoB100,CE d. IDL: apoB100E e. LDL; apoB100 ONLY f. All of the above 16. D: Chylomicrons are associated with apoB-48. HDL is apoA. LDL/VLDL is apoB100. ApoC, ApoA, and ApoE can MOVE AROUND DIFFERENT LIPOPROTEINS (ACE movement) via surface exchange.

HDL: ACE Chylomicrons: B48CE VLDL: B100CE IDL: B100E LDL: B100 Apoproteins can: 1) influence enzymatic activity 2)uptake of lipoproteins by receptors 3) be lipid transfer proteins.

17. What are functions of lipoprotein transport? a. Distribute TAGS for fuel + storage b. Deliver cholesterol and TAGS c. Manage cholesterol homeostasis d. All of the above 17. D: All of the above. Lipoproteins have a hydrophobic core of cholesterylesters (cholesterol + FA + hydroxyl) and TAGS with surrounded by a polar amphipathic phospholipids, unesterified cholesteriol, and proteins (apoplipoproteins). Apoplipoproteins act as ligands for cell receptors.

18. What are characteristics of lipoproteins? a. Transport lipids b. Core of unesterified cholesteryl and TAG c. Surface of phospholipids, sphingolipids, cholesterol, and apoproteins d. a & c 18. D. The core is of TAGs & esterfied cholesterolesters which are even more unipolar than cholesterol.