Hepatic fat metabolism, including lipogenic enzymes and signal transduction regulators, was assessed in livers of DPP4-deficient rats (DPP4-) with chronically elevated GLP-1 and in GLP-1-treated primary hepatocytes. The effect of chronic elevated GLP-1 on insulin sensitivity was measured using the hyperinsulinemic–euglycemic clamp.
Normal and high fat diet fed DPP4-rats displayed reduced hepatic triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid β-oxidation. In vitro studies demonstrated that these effects were directly induced by GLP-1. Mechanistically, GLP-1 increased cAMP in hepatocytes, resulting in the phosphorylation of cAMP-activated protein kinase (AMPK), a suppressor of lipogenesis. Indeed, hepatocytes expressing a dominant negative Ad-DN-AMPK displayed attenuated GLP-1 effects on AMPK phosphorylation and its downstream lipogenic targets. Importantly, normoglycemic DPP4-rats did not display improved hepatic insulin sensitivity in vivo, suggesting a direct effect of GLP-1 on fat metabolism. Finally, DPP4-rats expressed lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient stimuli.
GLP-1 suppresses hepatic lipogenesis via activation of the AMPK pathway. GLP-1 inhibitory effects on hepatic fat accumulation and nutrient-induced hepatic proinflammatory response suggest GLP-1 analogs as novel therapies for non-alcoholic fatty liver diseases.