Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis

Liver Int. 2011 Oct;31(9):1285-97. doi: 10.1111/j.1478-3231.2011.02462.x. Epub 2011 Feb 15.


Background/aims: High-fat dietary intake and low physical activity lead to insulin resistance, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Recent studies have shown an effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose metabolism, although GLP-1 receptors (GLP-1r) have not been found in human livers. The aim of this study was to investigate the presence of hepatic GLP-1r and the effect of exenatide, a GLP-1 analogue, on hepatic signalling.

Methods: The expression of GLP-1r was evaluated in human liver biopsies and in the livers of high-fat diet-treated rats. The effect of exenatide (100 nM) was evaluated in hepatic cells of rats fed 3 months with the high-fat diet.

Results: GLP-1r is expressed in human hepatocytes, although reduced in patients with NASH. Similarly, in rats with NASH resulted from 3 months of the high-fat diet, we found a decreased expression of GLP-1r and peroxisome proliferator-activated receptor γ (PPARγ), and reduced peroxisome proliferator-activated receptor α (PPARα) activity. Incubation of hepatocytes with exenatide increased PPARγ expression, which also exerted an insulin-sensitizing action by reducing JNK phosphorylation. Moreover, exenatide increased protein kinase A (PKA) activity, Akt and AMPK phosphorylation and determined a PKA-dependent increase of PPARα activity.

Conclusions: GLP-1 has a direct effect on hepatocytes, by activating genes involved in fatty acid β-oxidation and insulin sensitivity. GLP-1 analogues could be a promising treatment approach to improve hepatic insulin resistance in patients with NAFLD/NASH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Biopsy
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dietary Fats / metabolism*
  • Disease Models, Animal
  • Exenatide
  • Fatty Acids / metabolism
  • Fatty Liver / drug therapy*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Regulation
  • Glucagon-Like Peptide-1 Receptor
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin Resistance
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Non-alcoholic Fatty Liver Disease
  • Oxidation-Reduction
  • PPAR alpha / metabolism
  • PPAR gamma / metabolism
  • Peptides / pharmacology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism
  • Signal Transduction / drug effects*
  • Time Factors
  • Venoms / pharmacology*


  • Dietary Fats
  • Fatty Acids
  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • PPAR alpha
  • PPAR gamma
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Exenatide
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases