Hepatocyte Nuclear Factor 4α Prevents the Steatosis-to-NASH Progression by Regulating p53 and Bile Acid Signaling (in mice).
Hepatocyte Nuclear Factor 4α Prevents the Steatosis-to-NASH Progression by Regulating p53 and Bile Acid Signaling (in mice).
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肝细胞核因子4α通过调节p53和胆汁酸信号传导预防脂肪变性向NASH的进展（小鼠）。
DOI：
10.1002/hep.31604
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Xu Y;Zhu Y;Hu S;Xu Y;Stroup D;Pan X;Bawa FC;Chen S;Gopoju R;Yin L;Zhang Y
肝细胞核因子4α（HNF 4 α）在肝脏中高度富集，但其在肝脏脂肪变性（NAFL）发展为非酒精性脂肪性肝炎（NASH）中的作用尚未阐明。在这项研究中，我们研究了肝细胞HNF 4 α功能的获得或丧失对小鼠非酒精性脂肪性肝病（NAFLD）发生和进展的影响。过表达人HNF 4 α可预防高脂/胆固醇/果糖（HFCF）饮食诱导的脂肪性肝炎，而肝细胞HNF 4 α的缺失则具有相反的作用。HNF 4 α通过促进肝脏甘油三酯脂解、脂肪酸氧化和VLDL的分泌，抑制肝脏甘油三酯的蓄积。此外，HNF 4 α抑制NAFL向NASH的进展。在对照小鼠中，人HNF 4 α的过表达抑制了HFCF饮食诱导的脂肪性肝炎，但在肝细胞特异性p53−/−小鼠中没有。在缺乏肝脏Hnf 4 α的HFCF饲料喂养小鼠中，HNF 4 α的肝脏表达的重演靶向胆固醇7α-羟化酶和固醇12α-羟化酶使肝脏甘油三酯水平正常化并减轻脂肪性肝炎。目前的研究表明，肝细胞HNF 4 α通过协调脂解、p53和胆汁酸信号通路的调节来保护饮食诱导的NAFLD的发生和进展。靶向肝HNF 4 α可能有助于治疗NASH。
Hepatocyte nuclear factor 4α (HNF4α) is highly enriched in the liver, but its role in the progression of liver steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) has not been elucidated. In this study, we investigated the effect of gain or loss of hepatocyte HNF4α function on the development and progression of non-alcoholic fatty liver disease (NAFLD) in mice. Over-expression of human HNF4α protected against high fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis whereas loss of hepatocyte Hnf4α had opposite effects. HNF4α prevented hepatic triglyceride accumulation by promoting hepatic triglyceride lipolysis, fatty acid oxidation and VLDL secretion. Furthermore, HNF4α suppressed the progression of NAFL to NASH. Over-expression of human HNF4α inhibited HFCF diet-induced steatohepatitis in control mice but not in hepatocyte-specific p53−/− mice. In HFCF diet-fed mice lacking hepatic Hnf4α, recapitulation of hepatic expression of HNF4α targets cholesterol 7α-hydroxylase and sterol 12α-hydroxylase normalized hepatic triglyceride levels and attenuated steatohepatitis. The current study indicates that hepatocyte HNF4α protects against diet-induced development and progression of NAFLD by coordinating the regulation of lipolytic, p53 and bile acid signaling pathways. Targeting hepatic HNF4α may be useful for treatment of NASH.
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影响因子：
25.7
作者：
Derdak, Zoltan;Villegas, Kristine A.;Harb, Ragheb;Wu, Annie M.;Sousa, Aryanna;Wands, Jack R.
通讯作者：
Wands, Jack R.
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
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影响因子：
13.5
作者：
Charlton, N;Sreekumar, R;Nair, KS
通讯作者：
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