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Activation of intestinal hypoxia-inducible factor 2? during obesity contributes to hepatic steatosis.

ABSTRACT: 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-2? 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-2?-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2?. Intestine HIF-2? inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2? 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-2? could be a viable target for hepatic steatosis therapy.

SUBMITTER: Xie C

PROVIDER: S-EPMC6410352 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis.

Xie Cen C Yagai Tomoki T Luo Yuhong Y Liang Xianyi X Chen Tao T Wang Qiong Q Sun Dongxue D Zhao Jie J Ramakrishnan Sadeesh K SK Sun Lulu L Jiang Chunmei C Xue Xiang X Tian Yuan Y Krausz Kristopher W KW Patterson Andrew D AD Shah Yatrik M YM Wu Yue Y Jiang Changtao C Gonzalez Frank J FJ

Nature medicine 20171009 11

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-speci ...[more]

PMID: 29035368

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Project description:Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

Dataset Information

Activation of intestinal hypoxia-inducible factor 2? during obesity contributes to hepatic steatosis.

Publications

Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis.

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