title: Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice.
abstract: The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.
authors.affiliation: Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jinmi
authors.initials: J
authors.lastname: Lee
authors.forename: Seok-Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Seoung Wan
authors.initials: SW
authors.lastname: Chae
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Kim
authors.forename: Ji Hun
authors.initials: JH
authors.lastname: Choi
authors.forename: Ji Cheol
authors.initials: JC
authors.lastname: Bae
authors.forename: Se Eun
authors.initials: SE
authors.lastname: Park
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Rhee
authors.forename: Cheol-Young
authors.initials: CY
authors.lastname: Park
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Oh
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Park
authors.forename: Sun-Woo
authors.initials: SW
authors.lastname: Kim
authors.forename: Won-Young
authors.initials: WY
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D000077270:Exenatide; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D019308:Palmitic Acid / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014280:Triglycerides; D014688:Venoms; D019308:Palmitic Acid; D000077270:Exenatide; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose