Title |
Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis
|
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Published in |
Nature Medicine, October 2017
|
DOI | 10.1038/nm.4412 |
Pubmed ID | |
Authors |
Cen Xie, Tomoki Yagai, Yuhong Luo, Xianyi Liang, Tao Chen, Qiong Wang, Dongxue Sun, Jie Zhao, Sadeesh K Ramakrishnan, Lulu Sun, Chunmei Jiang, Xiang Xue, Yuan Tian, Kristopher W Krausz, Andrew D Patterson, Yatrik M Shah, Yue Wu, Changtao Jiang, Frank J Gonzalez |
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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Geographical breakdown
Country | Count | As % |
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United States | 10 | 26% |
Canada | 3 | 8% |
United Kingdom | 2 | 5% |
Spain | 2 | 5% |
Japan | 1 | 3% |
Singapore | 1 | 3% |
Mexico | 1 | 3% |
Georgia | 1 | 3% |
Ecuador | 1 | 3% |
Other | 1 | 3% |
Unknown | 15 | 39% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 27 | 71% |
Scientists | 9 | 24% |
Practitioners (doctors, other healthcare professionals) | 1 | 3% |
Science communicators (journalists, bloggers, editors) | 1 | 3% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 161 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 38 | 24% |
Student > Ph. D. Student | 24 | 15% |
Student > Master | 14 | 9% |
Professor | 10 | 6% |
Student > Bachelor | 9 | 6% |
Other | 29 | 18% |
Unknown | 37 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 36 | 22% |
Medicine and Dentistry | 24 | 15% |
Agricultural and Biological Sciences | 21 | 13% |
Immunology and Microbiology | 9 | 6% |
Neuroscience | 7 | 4% |
Other | 18 | 11% |
Unknown | 46 | 29% |