1. Academic Validation
  2. 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

  • Nat Med. 2017 Nov;23(11):1298-1308. doi: 10.1038/nm.4412.
Cen Xie 1 Tomoki Yagai 1 Yuhong Luo 1 Xianyi Liang 2 3 Tao Chen 4 Qiong Wang 1 Dongxue Sun 1 Jie Zhao 1 Sadeesh K Ramakrishnan 5 Lulu Sun 2 3 Chunmei Jiang 2 3 Xiang Xue 5 Yuan Tian 6 Kristopher W Krausz 1 Andrew D Patterson 6 Yatrik M Shah 5 Yue Wu 4 Changtao Jiang 2 3 Frank J Gonzalez 1
Affiliations

Affiliations

  • 1 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 3 Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
  • 4 Department of Internal Medicine, Key Laboratory of Environment and Genes Related to Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 5 Departments of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • 6 Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
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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