Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis
Nonalcoholic fatty liver disease has become the most typical chronic liver disease in Western countries, and limited therapeutic choices are available. Ideas uncovered a job for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals without or with weight problems says intestinal HIF-2a signaling was positively correlated with body-mass index and hepatic toxicity. The causality of the correlation was verified in rodents by having an intestine-specific disruption of Hif2a, by which high-fat-diet-caused hepatic steatosis and weight problems were substantially lower when compared with PT2385 control rodents. PT2385, a HIF-2a-specific inhibitor, had preventive and therapeutic effects on metabolic disorders which were determined by intestine HIF-2a. Intestine HIF-2a inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2a regulates ceramide metabolic process mainly in the salvage path, by positively controlling the expression of Neu3, the gene encoding neuraminidase 3. These results claim that intestinal HIF-2a might be a viable target for hepatic steatosis therapy.