Hepatic IRF6 alleviates liver steatosis and metabolic disorder by transcriptionally suppressing PPARgamma
Hepatic IRF6 alleviates liver steatosis and metabolic disorder by transcriptionally suppressing PPARgamma
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肝脏 IRF6 通过转录抑制 PPARgamma 减轻肝脏脂肪变性和代谢紊乱
作者：
Tong J;Han C. J;Zhang J. Z;He W. Z;Zhao G. J;Cheng X;Zhang L;Deng K. Q;Liu Y;Fan H. F;Tian S;Cai J;Huang Z;She Z. G;Zhang P;Li H.
非酒精性脂肪性肝病（NAFLD）已成为一种全球性流行病。一个巨大的和不断增长的未满足的治疗需求激发了该领域的许多研究。将基因表达综合库（GEO）中已发表的基因组数据与啮齿动物的NAFLD样本相结合，我们发现干扰素调节因子6（IRF 6）在高脂饮食（HFD）诱导的脂肪肝中显著下调。在目前的研究中，我们确定了肝细胞中的IRF 6作为肝脂肪变性（LS）的保护因子。在HFD攻击期间，hepaticIrf 6被启动子高甲基化抑制。在肝细胞特异性Irf 6基因敲除小鼠中，HFD诱导的LS的严重程度加重，而肝细胞特异性过表达Irf 6的转基因小鼠（IRF 6-HTG）在HFD喂养后表现出减轻的脂肪变性和代谢紊乱。体外机制研究表明，肝细胞IRF 6直接结合过氧化物酶体增殖物激活受体γ（PPARγ）基因的启动子，随后停止Ppar γ及其靶基因（例如，结论：Irf 6基因启动子区甲基化导致其表达下调，从而抑制Ppar γ及其靶基因的表达，导致脂质代谢异常。
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, hepaticIrf6was suppressed by promoter hypermethylation. Severity of HFD‐induced LS was exacerbated in hepatocyte‐specificIrf6knockout mice, whereas hepatocyte‐specific transgenic mice overexpressingIrf6(IRF6‐HTG) exhibited alleviated steatosis and metabolic disorder in response to HFD feeding. Mechanistic studiesin vitrodemonstrated that hepatocyte IRF6 directly binds to the promoter of the peroxisome proliferator‐activated receptor γ (PPARγ) gene and subsequently halts the transcription ofPparγand its target genes (e.g., genes that regulate lipogenesis and lipid acid uptake) under physiological conditions.Conclusion:Irf6is downregulated by promoter hypermethylation upon metabolic stimulus exposure, which fail to inhibitPparγand its targets, driving abnormalities of lipid metabolism.