High-fat diet mediates the formation of nonalcoholic fatty liver by modulating the AhR/miR-132/SIRT1 axis.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem affecting tens of millions of people worldwide. High-fat diet (HFD) has been reported to be associated with liver steatosis. However, the underlying mechanism remains unclear. The aim of this study was to explore the potential mechanism of HFD in hepatic steatosis. To investigate the potential induction of nonalcoholic fatty liver disease (NAFLD) by a high-fat diet (HFD), this study employed both in vitro free fatty acid (FFA) and in vivo HFD-induced NAFLD models. Serum samples from NAFLD patients were analyzed using ELISA and RT-qPCR to assess the expression of relevant indicators. In the in vitro experiments, cells were treated with 1 mM FFA for 24 hours, while in the in vivo experiments, mice were fed an HFD for 9 weeks. Lipid deposition in cells and liver tissues was examined through hematoxylin-eosin (HE) staining and Oil Red O staining. Furthermore, Western blotting, immunofluorescence, chromatin immunoprecipitation, immunohistochemistry, and RT-qPCR were utilized to systematically investigate the regulatory mechanisms underlying cellular and hepatic lipid deposition. The serum expression of AhR and miR-132 was increased and SIRT1 expression was decreased in NAFLD patients. In the high-fat-induced cell/mouse model of NAFLD, AhR and miR-132 expressions were significantly upregulated and negatively correlated with SIRT1 levels. Mechanistically, bioinformatics analysis and chromatin immunoprecipitation experiments confirmed that AhR could bind the miR-132 promoter to transcriptionally activate miR-132. miR-132 inhibitor transfection experiments confirmed that the downregulation of SIRT1 was dependent on miR-132 function. Our results suggest that HFD promotes hepatic lipid deposition through the AhR/miR-132/SIRT1 pathway and accelerates the development of NAFLD.