Activation of intestinal hypoxia-inducible factor 2? during obesity contributes to hepatic steatosis.

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-2? 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-2?-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2?. Intestine HIF-2? inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2? 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-2? could be a viable target for hepatic steatosis therapy.

SUBMITTER: Xie C 

PROVIDER: S-EPMC6410352 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature