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Activation of intestinal hypoxia-inducible factor 2α 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-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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Figure 1: Increased HIF-2α signaling in human ileum biopsies is correlated with obesity.
Figure 2: Intestine-specific HIF-2α disruption ameliorates the development of hepatic steatosis.
Figure 3: Intestinal HIF-2α deficiency reduces ceramide synthesis in the small intestine.
Figure 4: The ceramide-synthesis-related gene Neu3 is a novel HIF-2α target gene in the small intestine.
Figure 5: Administration of ceramide reverses the protective effects of intestinal HIF-2α inhibition on the development of HFD-induced hepatic steatosis.
Figure 6: PT2385 reverses HFD-induced hepatic steatosis.

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Acknowledgements

We thank L.G. Byrd, Y. Zhang, X. Gao, W. Liu, X. Gong, and T. Yan (National Cancer Institute) for assistance with the mouse studies, and B. Liu and X. Wu (Chinese Academy of Sciences) for help with the immunohistochemistry. This project was funded in part by the National Cancer Institute Intramural Research Program to F.J.G., grants from the National Key Research and Development Program of China (2016YFC0903100, 2016YFC0903102) to Changtao Jiang, the National Natural Science Foundation of China (31401011 and 81522007 to CT. J., and 81403007 to X.C.), National Institutes of Health grants ES022186 to A.D.P., and CA148828 and DK095201 to Y.M.S. S.K.R. was supported by NIDDK (K99DK110537). Q.W. was supported by the Peak Talent Foundation of Jiangsu Province Hospital of Chinese Medicine (Y2014RC18) and Jiangsu Government Scholarship for Overseas Studies. D.S. and J.Z. were supported by fellowships from the Chinese Scholarship Council.

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C.X., T.Y., Y.L., X.L., T.C., Q.W., D.S., J.Z., S.K.R., L.S., Chunmei Jiang, X.X., Y.T., and K.W.K. performed the research and analyzed the data. C.X., A.D.P., Y.M.S., Y.W., Changtao Jiang and F.J.G. designed and supervised the research. C.X., Changtao Jiang and F.J.G. wrote the manuscript.

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Correspondence to Yue Wu, Changtao Jiang or Frank J Gonzalez.

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Xie, C., Yagai, T., Luo, Y. et al. Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis. Nat Med 23, 1298–1308 (2017). https://doi.org/10.1038/nm.4412

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