MicroRNA-376b-3p ameliorates nonalcoholic fatty liver disease by targeting FGFR1 and regulating lipid oxidation in hepatocytes

Abstract

AimsNonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease whose molecular mechanisms remain unclear. This study aimed to explore the role and mechanisms of microRNA-376b-3p in NAFLD. Materials and methodsWe used a microarray to reveal hepatic microRNA expression profiles and validated their expression in cellular and mouse models via qRT–PCR. In vitro, the expression of microRNA-376b-3p was increased by a microRNA-376b-3p mimic and decreased by a microRNA-376b-3p inhibitor. The role and potential mechanisms of microRNA-376b-3p in NAFLD were investigated in mice injected with lentiviral vectors before high-fat diet (HFD) feeding, and the direct target gene was explored using a dual-luciferase reporter gene assay and confirmed by Western blotting. Key findingsMicroarray analysis and subsequent validation showed that the expression of microRNA-376b-3p was downregulated by nearly 90 % in the livers of HFD-fed mice and by >50 % in free fatty acid-stimulated hepatocytes. Overexpression of microRNA-376b-3p markedly ameliorated hepatic lipid accumulation, which was attributable to an increase in fatty acid oxidation. Conversely, inhibition of miR-376b-3p exhibited the opposite effects. The luciferase reporter assay indicated that Fgfr1 is a direct target gene of miR-376b-3p. Fgfr1 intervention eliminated the effect of miR-376b-3p on the lipid oxidation pathway and hepatocyte steatosis, which suggests that miR-376b-3p regulates fatty acid oxidation by targeting Fgfr1 to influence NAFLD development. SignificancemiR-376b-3p was downregulated in NAFLD and has a novel regulatory role in lipid oxidation through a miR-376b-3p-Fgfr1-dependent mechanism.Thus, miR-376b-3p may serve as a potential diagnostic marker or therapeutic target for NAFLD.