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.