Abstract
AP-1
THE DIVERSIFIED ROLE OF LIVER FAT AND HEPATOKINES IN METABOLIC DISEASES HORNG-YIH OU Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Taiwan.
Metabolic diseases such as obesity, diabetes, and cardiovascular diseases are increasingly public health issues in modern society. The accumulation of ectopic fat plays an important role in the pathogenesis of these diseases. During the past years, my research interest has been focused on the diverse roles of liver fat accumulation (fatty liver) and hormones secreted by liver (hepatokines) in metabolic diseases. In this talk, I will first present our researches on the hepatokines, fetuin-A. We found hyperglycemia-related endoplasmic reticulum stress induced the expression of fetuin-A to develop insulin resistance. In humans, serum fetuin-A concentrations are elevated in impaired glucose tolerance and newly-diagnosed type 2 diabetes, and the presence of NAFLD significantly increases fetuin-A levels in normoglycemia and prediabetes. Both diabetes and fetuin-A are independently associated with increased risk of arterial stiffness. Furthmore, pharmacologic treatment with a selective G proteincoupled receptor 40 agonist, GW-9508, decreases the hepatic expression of fetuin-A to improve insulin sensitivity and hepatic steatosis in diabetic mice. Then, I will discuss another hepatokine, hepassocin. We found that subjects with NAFLD and prediabetes/diabetes have a higher serum hepassocin level than those without it. Overexpression of hepassocin induces hepatic steatois and steatohepatitis through an ERK1/2-dependent pathway. Hepassocin also induces insulin resitance in mice model. Furtheromore, in subjects with hyperlgycemic crisis, we demonstrated that increased hepassocin secretion might offset the deleterious effects of hyperglycemia on hepatocytes. Finally, I will show our collaborative work with NTUH on fatty liver and fatty pancreas. We found the prevalence of fatty pancreas is high in the general population. Both diabetes and NAFLD are important independent associated factors of fatty pancreas. With an increase in glycemia, a VLJQL¿FDQWO\ JUHDWHU SURSRUWLRQ RI VXEMHFWV KDV 1$)/' DQG IDWW\ SDQFUHDV ,QWHUHVWLQJO\ ERWK 1$)/' and fatty pancreas are associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors. Taken together, our research suggests that hepatokines play an important role in the development of fatty liver, pathogenesis of insulin resistance and arterial stiffness, and protection from hyperglycemia-related hepatic injury. In addition, fatty liver and fatty pancreas have a synergistic effect in the pathogenesis of diabetes. 103
