| First Author | Xie C | Year | 2017 |
| Journal | Nat Med | Volume | 23 |
| Issue | 11 | Pages | 1298-1308 |
| PubMed ID | 29035368 | Mgi Jnum | J:252613 |
| Mgi Id | MGI:6103551 | Doi | 10.1038/nm.4412 |
| Citation | Xie C, et al. (2017) Activation of intestinal hypoxia-inducible factor 2alpha during obesity contributes to hepatic steatosis. Nat Med 23(11):1298-1308 |
| abstractText | 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-2alpha 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-2alpha-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2alpha. Intestine HIF-2alpha inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2alpha 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-2alpha could be a viable target for hepatic steatosis therapy. |
