Sphingosine d18:1 Promotes Nonalcoholic Steatohepatitis by Inhibiting Macrophage HIF-2α

Abstract Non-alcoholic steatohepatitis (NASH) is a severe type of the non-alcoholic fatty liver disease (NAFLD). NASH is a growing global health concern due to its increasing morbidity, lack of well-defined biomarkers and lack of clinically effective treatments. Using metabolomic analysis, the most significantly changed active lipid sphingosine d18:1 [So(d18:1)] was selected from NASH patients. So(d18:1) inhibits macrophage HIF-2α as a direct inhibitor and promotes the activation of NLRP3 inflammasome. Macrophage-specific HIF-2α knockout and overexpression mice verified the effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviated liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α was a potential drug target for NASH treatment. Overall, this study confirms that So(d18:1) promotes NASH and clarifies that So(d18:1) inhibits the transcriptional activity of HIF-2α in liver macrophages by suppressing the interaction of HIF-2α with ARNT, suggesting that macrophage HIF-2α may be a new target for the treatment of NASH.