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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1298-1308 |
| Number of pages | 11 |
| Journal | Nature Medicine |
| Volume | 23 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2017 |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
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Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis. / Xie, Cen; Yagai, Tomoki; Luo, Yuhong; Liang, Xianyi; Chen, Tao; Wang, Qiong; Sun, Dongxue; Zhao, Jie; Ramakrishnan, Sadeesh K.; Sun, Lulu; Jiang, Chunmei; Xue, Xiang; Tian, Yuan; Krausz, Kristopher W.; Patterson, Andrew D.; Shah, Yatrik M.; Wu, Yue; Jiang, Changtao; Gonzalez, Frank J.
In: Nature Medicine, Vol. 23, No. 11, 01.11.2017, p. 1298-1308.Research output: Contribution to journal › Article
TY - JOUR
T1 - Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis
AU - Xie, Cen
AU - Yagai, Tomoki
AU - Luo, Yuhong
AU - Liang, Xianyi
AU - Chen, Tao
AU - Wang, Qiong
AU - Sun, Dongxue
AU - Zhao, Jie
AU - Ramakrishnan, Sadeesh K.
AU - Sun, Lulu
AU - Jiang, Chunmei
AU - Xue, Xiang
AU - Tian, Yuan
AU - Krausz, Kristopher W.
AU - Patterson, Andrew D.
AU - Shah, Yatrik M.
AU - Wu, Yue
AU - Jiang, Changtao
AU - Gonzalez, Frank J.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85033220110&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033220110&partnerID=8YFLogxK
U2 - 10.1038/nm.4412
DO - 10.1038/nm.4412
M3 - Article
C2 - 29035368
AN - SCOPUS:85033220110
VL - 23
SP - 1298
EP - 1308
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 11
ER -