Activation of intestinal hypoxia-inducible factor 2α 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-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.

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

“…HIF2‐alpha is a necessary component of the insulin response mediated by VEGF in the liver. Fat deposition and steatohepatitis in the liver are increased in the absence of HIF2‐alpha …”

Metabolic Profiling of the Novel Hypoxia-Inducible Factor 2α Inhibitor PT2385 In Vivo and In Vitro

“…However, neither PT2385 treatment nor intestinal Hif2a disruption affects hepatic HIF-2a signaling (Xie et al, 2017). The link between intestine HIF-2a and bile acid synthesis needs further investigation.…”

“…PT2385 is a selective and potent HIF-2α inhibitor and showed promising efficacy in the treatment of advanced ccRCC and metabolic disease (Wishart, 2016;Xie et al, 2017). PT2385 was rapidly absorbed with a median t max of 2 h and a mean t 1/2 of 17 h in ccRCC patients (Courtney et al, 2017).…”

“…Male Hif2a fl/fl (control) and Hif2a ∆IE (intestine-specific Hif2a disruption) mice were generated and maintained as previously described (Xie et al, 2017). Mice were housed in a temperature-and humidity-controlled room and maintained under a standard 12 h light/12 h dark cycle with water and chow provided ad libitum.…”

“…There is another phase II study of PT2385 for patients with recurrent glioblastoma. Besides antineoplastic activity, a recent report also showed that the inhibition of intestinal HIF-2α signaling by PT2385 substantially prevents and reverses obesity, insulin resistance and hepatic steatosis in mice (Xie et al, 2017).…”