2. Academic Validation
  3. 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.
PMID: 29035368 DOI: 10.1038/nm.4412
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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