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

C Xie, T Yagai, Y Luo, X Liang, T Chen, Q Wang… - Nature medicine, 2017 - nature.com
C Xie, T Yagai, Y Luo, X Liang, T Chen, Q Wang, D Sun, J Zhao, SK Ramakrishnan, L Sun…
Nature medicine, 2017nature.com
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 …
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.
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