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.

中文翻译：

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肥胖期间肠道缺氧诱导因子 2α 的激活会导致肝脏脂肪变性。


非酒精性脂肪肝正在成为西方国家最常见的慢性肝病，可用的治疗选择有限。在这里，我们发现了肠道缺氧诱导因子（HIF）在肝脂肪变性中的作用。对肥胖或不肥胖个体的人体肠道活检显示，肠道 HIF-2α 信号传导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脏脂肪变性和肥胖显着降低。 PT2385是一种HIF-2α特异性抑制剂，对依赖肠道HIF-2α的代谢紊乱具有预防和治疗作用。肠道 HIF-2α 抑制显着降低肠道和血清神经酰胺水平。从机制上讲，肠道 HIF-2α 主要通过挽救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。