Exendin-4 improves steatohepatitis by increasing Sirt1 expression in high-fat diet-induced obese C57BL/6J mice

PLoS One. 2012;7(2):e31394. doi: 10.1371/journal.pone.0031394. Epub 2012 Feb 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Body Weight / drug effects
  • Cell Line, Tumor
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diet, High-Fat*
  • Exenatide
  • Fatty Liver / blood
  • Fatty Liver / drug therapy*
  • Fatty Liver / genetics
  • Fatty Liver / pathology
  • Feeding Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Homeostasis / drug effects
  • Homeostasis / genetics
  • Humans
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver / drug effects
  • Liver / enzymology
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism
  • Oxidation-Reduction / drug effects
  • Palmitic Acid / pharmacology
  • Peptides / pharmacology
  • Peptides / therapeutic use*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Triglycerides / blood
  • Venoms / pharmacology
  • Venoms / therapeutic use*

Substances

  • Cytokines
  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Receptors, Glucagon
  • Triglycerides
  • Venoms
  • Palmitic Acid
  • Exenatide
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Glucose