Hepatic IRF6 alleviates liver steatosis and metabolic disorder by transcriptionally suppressing PPARγ

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become a worldwide epidemic. A large and growing unmet therapeutic need has inspired numerous studies in the field. Integrating the published genomic data available in the Gene Expression Omnibus with NAFLD samples from rodents, we discovered that interferon regulatory factor 6 (IRF6) is significantly suppressed in high‐fat diet (HFD)‐induced fatty liver. In the current study, we identified IRF6 in hepatocytes as a protective factor in liver steatosis. During HFD challenge, hepatic Irf6 was suppressed by promoter hypermethylation. The severity of HFD‐induced liver steatosis was exacerbated in hepatocyte‐specific Irf6 knockout mice, whereas hepatocyte‐specific transgenic mice overexpressing Irf6 (IRF6‐HTG) exhibited alleviated responses to HFD feeding. Mechanistic studies in vitro demonstrated that hepatic IRF6 directly binds to the promoter of the peroxisome proliferator‐activated receptor γ (PPARγ) gene and subsequently halts the transcription of Pparγ and its target genes (e.g., genes that regulate lipogenesis and lipid acid uptake) under physiological conditions. After metabolic stimulus exposure, the insufficient production of IRF6 in hepatocytes led to a failure to inhibit Pparγ and its targets, driving abnormalities of lipid metabolism.

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