Why the study?
NASH is a growing global health concern with increasing morbidity, but lacks well-defined biomarkers and clinically effective treatments.
Sphingosine d18:1 promotes NASH by inhibiting macrophage HIF-2α, and stabilizing HIF-2α with FG-4592 alleviates liver inflammation and fibrosis in preclinical models.
May support macrophage HIF-2α as NASH target; hypothesis-generating, needs clinical trials before practice change.
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.
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Jiang et al. (2023) studied this question.
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