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Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice

Author

Listed:
  • Weitao Zhang

    (Zhejiang University
    China Pharmaceutical University)

  • Junfeng Lu

    (Capital Medical University)

  • Lianshun Feng

    (China Pharmaceutical University)

  • Hanyue Xue

    (China Pharmaceutical University)

  • Shiyang Shen

    (China Pharmaceutical University)

  • Shuiqing Lai

    (Guangdong Academy of Medical Sciences)

  • PingPing Li

    (Diabetes Research Center of Chinese Academy of Medical Sciences)

  • Ping Li

    (China Pharmaceutical University)

  • Jian Kuang

    (Guangdong Academy of Medical Sciences)

  • Zhiwei Yang

    (Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical Collage (PUMC))

  • Xiaojun Xu

    (Zhejiang University
    China Pharmaceutical University)

Abstract

Sonic hedgehog (SHH) and heat shock protein 90β (HSP90β) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90β is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90β ubiquitylation through deubiquitylase USP31, thus preventing HSP90β degradation and promoting hepatic lipid synthesis. HSP90β significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90β axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90β-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.

Suggested Citation

  • Weitao Zhang & Junfeng Lu & Lianshun Feng & Hanyue Xue & Shiyang Shen & Shuiqing Lai & PingPing Li & Ping Li & Jian Kuang & Zhiwei Yang & Xiaojun Xu, 2024. "Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45520-8
    DOI: 10.1038/s41467-024-45520-8
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    References listed on IDEAS

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    1. Ruben Garcia-Martin & Guoxiao Wang & Bruna B. Brandão & Tamires M. Zanotto & Samah Shah & Sandip Kumar Patel & Birgit Schilling & C. Ronald Kahn, 2022. "MicroRNA sequence codes for small extracellular vesicle release and cellular retention," Nature, Nature, vol. 601(7893), pages 446-451, January.
    2. Xiao-Yi Lu & Xiong-Jie Shi & Ao Hu & Ju-Qiong Wang & Yi Ding & Wei Jiang & Ming Sun & Xiaolu Zhao & Jie Luo & Wei Qi & Bao-Liang Song, 2020. "Feeding induces cholesterol biosynthesis via the mTORC1–USP20–HMGCR axis," Nature, Nature, vol. 588(7838), pages 479-484, December.
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