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SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation

Author

Listed:
  • Pingping Lai

    (Peking University)

  • Guolin Miao

    (Peking University
    Peking University Third Hospital)

  • Yinqi Zhao

    (Peking University)

  • Yufei Han

    (Peking University)

  • Yanwei Li

    (China Medical University)

  • Yiran Liu

    (Peking University)

  • Jiabao Guo

    (Peking University)

  • Wenxi Zhang

    (Peking University)

  • Xin Guo

    (Peking University Third Hospital)

  • Yitong Xu

    (Peking University)

  • Lianxin Zhang

    (Peking University)

  • Gonglie Chen

    (Peking University)

  • Zihao Zhou

    (Peking University)

  • Si Mei

    (Peking University)

  • Jingxuan Chen

    (Peking University)

  • Jinxuan Chen

    (Peking University)

  • Luzheng Xu

    (Peking University)

  • Chong Zhang

    (China Medical University)

  • Yang Ding

    (China Medical University)

  • Xiaoguang Dou

    (China Medical University)

  • Shengmei Wen

    (NGGT (Suzhou) Biotechnology Co. Ltd)

  • Sin Man Lam

    (Chinese Academy of Sciences
    Lipidall Technologies Company Limited)

  • Guanghou Shui

    (Chinese Academy of Sciences)

  • Yuhui Wang

    (Peking University)

  • Wei Huang

    (Peking University)

  • Dongyu Zhao

    (Peking University)

  • Xunde Xian

    (Peking University
    Peking University Third Hospital)

Abstract

Scavenger receptor class A member 3 (SR-A3) is implicated in metabolic diseases; however, the relationship between SR-A3 and metabolic dysfunction-associated fatty liver disease (MAFLD) has not been documented. Here, we show that hepatic SR-A3 expression is significantly reduced in human and animal models in the context of MAFLD. Genetic inhibition of SR-A3 in hamsters elicits hyperlipidemia, hyperglycemia, insulin resistance, and hepatic steatosis under chow-diet condition, yet escalates in diet-induced MAFLD. Mechanistically, SR-A3 ablation enhances E3 ligase XIAP-mediated proteasomal ubiquitination of PTEN, leading to AKT hyperactivation. By contrast, hepatic overexpression of human SR-A3 is sufficient to attenuate metabolic disorders in WT hamsters fed a high-fat-high-cholesterol diet and ob/ob mice via suppressing the XIAP/PTEN/AKT axis. In parallel, pharmacological intervention by PTEN agonist oroxin B or lipid lowering agent ezetimibe differentially corrects MAFLD in hamsters.

Suggested Citation

  • Pingping Lai & Guolin Miao & Yinqi Zhao & Yufei Han & Yanwei Li & Yiran Liu & Jiabao Guo & Wenxi Zhang & Xin Guo & Yitong Xu & Lianxin Zhang & Gonglie Chen & Zihao Zhou & Si Mei & Jingxuan Chen & Jinx, 2025. "SR-A3 suppresses AKT activation to protect against MAFLD by inhibiting XIAP-mediated PTEN degradation," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57585-0
    DOI: 10.1038/s41467-025-57585-0
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