Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α.
Nat Commun
; 15(1): 4755, 2024 Jun 04.
Article
in En
| MEDLINE
| ID: mdl-38834568
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 d181 [So(d181)] is selected from NASH patients. So(d181) inhibits macrophage HIF-2α as a direct inhibitor and promotes the inflammatory factors secretion. Male macrophage-specific HIF-2α knockout and overexpression mice verified the protective effect of HIF-2α on NASH progression. Importantly, the HIF-2α stabilizer FG-4592 alleviates liver inflammation and fibrosis in NASH, which indicated that macrophage HIF-2α is a potential drug target for NASH treatment. Overall, this study confirms that So(d181) promotes NASH and clarifies that So(d181) 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 potential target for the treatment of NASH.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sphingosine
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Mice, Knockout
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Basic Helix-Loop-Helix Transcription Factors
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Non-alcoholic Fatty Liver Disease
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Macrophages
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Nat Commun
Year:
2024
Document type:
Article