Jingjing Tong1,2, Cui-Juan Han3, Jia-Zhen Zhang1, Wen-Zhi He2, Guo-Jun Zhao1, Xu Cheng3, Lei Zhang1, Ke-Qiong Deng1,4, Ye Liu4,5, Hui-Fen Fan4, Song Tian1,4, Jingjing Cai6, Zan Huang2,4, Zhi-Gang She1,3,4, Peng Zhang4,5, Hongliang Li1,3,4,7. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China. 2. College of Life Sciences, Wuhan University, Wuhan, China. 3. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China. 4. Institute of Model Animal of Wuhan University, Wuhan, China. 5. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. 6. Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China. 7. School of Basic Medical Sciences, Wuhan University, Wuhan, China.
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 (GEO) with NAFLD samples from rodents, we discovered that interferon regulatory factor 6 (IRF6) is significantly downregulated in high-fat diet (HFD)-induced fatty liver. In the current study, we identified IRF6 in hepatocytes as a protective factor in liver steatosis (LS). During HFD challenge, hepatic Irf6 was suppressed by promoter hypermethylation. Severity of HFD-induced LS was exacerbated in hepatocyte-specific Irf6 knockout mice, whereas hepatocyte-specific transgenic mice overexpressing Irf6 (IRF6-HTG) exhibited alleviated steatosis and metabolic disorder in response to HFD feeding. Mechanistic studies in vitro demonstrated that hepatocyte 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. Conclusion: Irf6 is downregulated by promoter hypermethylation upon metabolic stimulus exposure, which fail to inhibit Pparγ and its targets, driving abnormalities of lipid metabolism.
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 (GEO) with NAFLD samples from rodents, we discovered that interferon regulatory factor 6 (IRF6) is significantly downregulated in high-fat diet (HFD)-induced fatty liver. In the current study, we identified IRF6 in hepatocytes as a protective factor in liver steatosis (LS). During HFD challenge, hepatic Irf6 was suppressed by promoter hypermethylation. Severity of HFD-induced LS was exacerbated in hepatocyte-specific Irf6 knockout mice, whereas hepatocyte-specific transgenic mice overexpressing Irf6 (IRF6-HTG) exhibited alleviated steatosis and metabolic disorder in response to HFD feeding. Mechanistic studies in vitro demonstrated that hepatocyte 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. Conclusion:Irf6 is downregulated by promoter hypermethylation upon metabolic stimulus exposure, which fail to inhibit Pparγ and its targets, driving abnormalities of lipid metabolism.