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Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling

Author

Listed:
  • Jing Zhong

    (Shanghai University of Traditional Chinese Medicine
    Zhejiang University School of Medicine)

  • Xiaofang He

    (Shanghai University of Traditional Chinese Medicine)

  • Xinxin Gao

    (Shanghai University of Traditional Chinese Medicine)

  • Qiaohong Liu

    (Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine)

  • Yu Zhao

    (Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine)

  • Ying Hong

    (Shanghai University of Traditional Chinese Medicine)

  • Weize Zhu

    (Shanghai University of Traditional Chinese Medicine)

  • Juan Yan

    (Shanghai University of Traditional Chinese Medicine)

  • Yifan Li

    (Shanghai University of Traditional Chinese Medicine)

  • Yan Li

    (Shanghai University of Traditional Chinese Medicine)

  • Ningning Zheng

    (Shanghai University of Traditional Chinese Medicine)

  • Yiyang Bao

    (Shanghai University of Traditional Chinese Medicine)

  • Hao Wang

    (Shanghai University of Traditional Chinese Medicine)

  • Junli Ma

    (Shanghai University of Traditional Chinese Medicine)

  • Wenjin Huang

    (Shanghai University of Traditional Chinese Medicine)

  • Zekun Liu

    (Shanghai University of Traditional Chinese Medicine)

  • Yuanzhi Lyu

    (University of California, Davis)

  • Xisong Ke

    (Shanghai University of Traditional Chinese Medicine)

  • Wei Jia

    (Center for Translational Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
    Hong Kong Baptist University)

  • Cen Xie

    (Chinese Academy of Sciences)

  • Yiyang Hu

    (Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine)

  • Lili Sheng

    (Shanghai University of Traditional Chinese Medicine)

  • Houkai Li

    (Shanghai University of Traditional Chinese Medicine)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.

Suggested Citation

  • Jing Zhong & Xiaofang He & Xinxin Gao & Qiaohong Liu & Yu Zhao & Ying Hong & Weize Zhu & Juan Yan & Yifan Li & Yan Li & Ningning Zheng & Yiyang Bao & Hao Wang & Junli Ma & Wenjin Huang & Zekun Liu & Y, 2023. "Hyodeoxycholic acid ameliorates nonalcoholic fatty liver disease by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41061-8
    DOI: 10.1038/s41467-023-41061-8
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    References listed on IDEAS

    as
    1. Xiaojiao Zheng & Tianlu Chen & Aihua Zhao & Zhangchi Ning & Junliang Kuang & Shouli Wang & Yijun You & Yuqian Bao & Xiaojing Ma & Haoyong Yu & Jian Zhou & Miao Jiang & Mengci Li & Jieyi Wang & Xiaohui, 2021. "Hyocholic acid species as novel biomarkers for metabolic disorders," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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