Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α

Jialin Xia, Hong Chen, Xiaoxiao Wang, Weixuan Chen, Jun Lin, Feng Xu, Qixing Nie, Chuan Ye, Bitao Zhong, Min Zhao, Chuyu Yun, Guangyi Zeng, Yuejian Mao, Yongping Wen, Xuguang Zhang, Sen Yan, Xuemei Wang, Lulu Sun, Feng Liu, Chao Zhong, Pengyan Xia, Changtao Jiang, Huiying Rao () and Yanli Pang ()
Additional contact information
Jialin Xia: Peking University
Hong Chen: Peking University
Xiaoxiao Wang: Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis
Weixuan Chen: Peking University Third Hospital
Jun Lin: Peking University
Feng Xu: Peking University
Qixing Nie: Peking University
Chuan Ye: Peking University
Bitao Zhong: Peking University
Min Zhao: Peking University Third Hospital
Chuyu Yun: Peking University Third Hospital
Guangyi Zeng: Peking University
Yuejian Mao: Peking University
Yongping Wen: Mengniu Institute of Nutrition Science
Xuguang Zhang: Mengniu Institute of Nutrition Science
Sen Yan: Peking University Third Hospital
Xuemei Wang: Peking University
Lulu Sun: Peking University
Feng Liu: Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis
Chao Zhong: Peking University
Pengyan Xia: Peking University
Changtao Jiang: Peking University
Huiying Rao: Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis
Yanli Pang: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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)] is selected from NASH patients. So(d18:1) 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(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 potential target for the treatment of NASH.

Date: 2024
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DOI: 10.1038/s41467-024-48954-2

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