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

Author

Listed:
  • Jialin Xia

    (Peking University
    Peking University Third Hospital
    Peking University
    Peking University Third Hospital)

  • Hong Chen

    (Peking University
    Peking University Third Hospital
    Peking University
    Peking University Third Hospital)

  • Xiaoxiao Wang

    (Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis)

  • Weixuan Chen

    (Peking University Third Hospital
    Peking University)

  • Jun Lin

    (Peking University
    Peking University Third Hospital
    Peking University)

  • Feng Xu

    (Peking University
    Peking University Third Hospital
    Peking University)

  • Qixing Nie

    (Peking University
    Peking University Third Hospital
    Peking University)

  • Chuan Ye

    (Peking University
    Peking University Third Hospital
    Peking University)

  • Bitao Zhong

    (Peking University)

  • Min Zhao

    (Peking University Third Hospital
    Peking University)

  • Chuyu Yun

    (Peking University Third Hospital
    Peking University)

  • Guangyi Zeng

    (Peking University
    Peking University Third Hospital
    Peking University
    Peking University Third Hospital)

  • Yuejian Mao

    (Peking University)

  • Yongping Wen

    (Mengniu Institute of Nutrition Science)

  • Xuguang Zhang

    (Mengniu Institute of Nutrition Science
    The Chinese Academy of Sciences)

  • Sen Yan

    (Peking University Third Hospital
    Peking University)

  • Xuemei Wang

    (Peking University
    Peking University Third Hospital
    Peking University)

  • Lulu Sun

    (Peking University
    Peking University Third Hospital)

  • 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
    Peking University Third Hospital
    Peking University
    Peking University)

  • Huiying Rao

    (Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis)

  • Yanli Pang

    (Peking University
    Peking University Third Hospital
    Peking University)

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.

Suggested Citation

  • 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, 2024. "Sphingosine d18:1 promotes nonalcoholic steatohepatitis by inhibiting macrophage HIF-2α," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48954-2
    DOI: 10.1038/s41467-024-48954-2
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    References listed on IDEAS

    as
    1. Bo Chen & Lulu Sun & Guangyi Zeng & Zhe Shen & Kai Wang & Limin Yin & Feng Xu & Pengcheng Wang & Yong Ding & Qixing Nie & Qing Wu & Zhiwei Zhang & Jialin Xia & Jun Lin & Yuhong Luo & Jie Cai & Kristop, 2022. "Gut bacteria alleviate smoking-related NASH by degrading gut nicotine," Nature, Nature, vol. 610(7932), pages 562-568, October.
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