Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis.
Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis.
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肥胖期间肠道缺氧诱导因子 2 α 的激活导致肝脂肪变性
DOI：
10.1038/nm.4412
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发表时间：
2017-11
期刊：
影响因子：
82.9
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Xie C;Yagai T;Luo Y;Liang X;Chen T;Wang Q;Sun D;Zhao J;Ramakrishnan SK;Sun L;Jiang C;Xue X;Tian Y;Krausz KW;Patterson AD;Shah YM;Wu Y;Jiang C;Gonzalez FJ
在西方国家，非酒精性脂肪性肝病正成为最常见的慢性肝病，治疗选择有限。本研究揭示了肠道缺氧诱导因子（HIF）在肝脂肪变性中的作用。来自肥胖或非肥胖个体的人体肠道活检显示，肠道HIF-2α信号与体重指数和肝毒性呈正相关。这种相关性的因果关系在Hif2a肠道特异性破坏的小鼠中得到了验证，与对照小鼠相比，高脂肪饮食诱导的肝脂肪变性和肥胖显著降低。PT2385是一种HIF-2α特异性抑制剂，对肠道HIF-2α依赖性代谢紊乱具有预防和治疗作用。肠道HIF-2α抑制显著降低肠道和血清神经酰胺水平。在机制上，肠道HIF-2α主要从救助途径调节神经酰胺代谢，通过正向调节Neu3（编码神经氨酸酶3的基因）的表达。这些结果表明，肠道HIF-2α可能是肝脂肪变性治疗的可行靶点。
Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.
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影响因子：
30.3
作者：
Kelly CJ;Zheng L;Campbell EL;Saeedi B;Scholz CC;Bayless AJ;Wilson KE;Glover LE;Kominsky DJ;Magnuson A;Weir TL;Ehrentraut SF;Pickel C;Kuhn KA;Lanis JM;Nguyen V;Taylor CT;Colgan SP
通讯作者：
Colgan SP
影响因子：
29.4
作者：
Cummins, Eoin P.;Seeballuck, Fergal;Taylor, Cormac T.
通讯作者：
Taylor, Cormac T.
影响因子：
5.6
作者：
Giussani P;Tringali C;Riboni L;Viani P;Venerando B
通讯作者：
Venerando B
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
肠道选择性法尼醇 X 受体抑制可改善肥胖相关的代谢功能障碍。
影响因子：
16.6
作者：
Jiang C;Xie C;Lv Y;Li J;Krausz KW;Shi J;Brocker CN;Desai D;Amin SG;Bisson WH;Liu Y;Gavrilova O;Patterson AD;Gonzalez FJ
通讯作者：
Gonzalez FJ