Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice

Am J Physiol Gastrointest Liver Physiol. 2012 Apr 15;302(8):G762-72. doi: 10.1152/ajpgi.00476.2011. Epub 2012 Jan 19.


These preclinical studies aimed to 1) increase our understanding the dietary induction of nonalcoholic steatohepatitis (NASH), and, 2) further explore the utility and mechanisms of glucagon-like peptide-1 receptor (GLP-1R) agonism in NASH. We compared the effects of a high trans-fat (HTF) or high lard fat (HLF) diet on key facets of nonalcoholic fatty liver disease (NAFLD)/NASH in Lep(ob)/Lep(ob) and C57BL6J (B6) mice. Although HLF-fed mice experienced overall greater gains in weight and adiposity, the addition of trans-fat better mirrored pathophysiological features of NASH (e.g., hepatomegaly, hepatic lipid, and fibrosis). Administration of AC3174, an exenatide analog, and GLP-1R agonist to Lep(ob)/Lep(ob) and B6 ameliorated hepatic endpoints in both dietary models. Next, we assessed whether AC3174-mediated improvements in diet-induced NASH were solely due to weight loss in HTF-fed mice. AC3174-treatment significantly reduced body weight (8.3%), liver mass (14.2%), liver lipid (12.9%), plasma alanine aminotransferase, and triglycerides, whereas a calorie-restricted, weight-matched group demonstrated only modest nonsignificant reductions in liver mass (9%) and liver lipid (5.1%) relative to controls. Treatment of GLP-1R-deficient (GLP-1RKO) mice with AC3174 had no effect on body weight, adiposity, liver or plasma indices pointing to the GLP-1R-dependence of AC3174's effects. Interestingly, the role of endogenous GLP-1Rs in NASH merits further exploration as the GLP-1RKO model was protected from the deleterious hepatic effects of HTF. Our pharmacological data further support the clinical evaluation of the utility of GLP-1R agonists for treatment of NASH.

MeSH terms

  • Animals
  • Body Composition / physiology
  • Body Weight / drug effects
  • Diet
  • Diet, Fat-Restricted
  • Diet, High-Fat
  • Endpoint Determination
  • Fatty Liver / chemically induced
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression / drug effects
  • Glucagon-Like Peptide-1 Receptor
  • Hormones / blood
  • Leptin / genetics
  • Lipids / chemistry
  • Liver / metabolism
  • Liver / pathology
  • Liver Function Tests
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Non-alcoholic Fatty Liver Disease
  • Peptides / therapeutic use*
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / genetics
  • Trans Fatty Acids / pharmacology
  • Weight Loss / drug effects


  • AC3174
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Hormones
  • Leptin
  • Lipids
  • Peptides
  • Receptors, Glucagon
  • Trans Fatty Acids