IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45520-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45520-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-45520-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yumeng Peng & Qiang Zeng & Luming Wan & Enhao Ma & Huilong Li & Xiaopan Yang & Yanhong Zhang & Linfei Huang & Haotian Lin & Jiangyue Feng & Yixin Xu & Jingfei Li & Muyi Liu & Jing Liu & Changqin Lin &, 2021. "GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Xinyan Zhou & Mengchao Yu & Luzhen Ma & Jinyu Fu & Jingwei Guo & Jieqiong Lei & Zheng Fu & Yong Fu & Qipeng Zhang & Chen-Yu Zhang & Xi Chen, 2022. "In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    3. Jinhong Xu & Le Cui & Jiaqi Wang & Shasha Zheng & Huahua Zhang & Shuo Ke & Xiaoqin Cao & Yanteng Shi & Jing Li & Ke Zen & Antonio Vidal-Puig & Chen-Yu Zhang & Liang Li & Xiaohong Jiang, 2023. "Cold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Zitao Zhao & Yanhong Guo & Lei Zhuang & Yongbao Wu & Jing Liu & Junting Cao & Zhanyue Wu & Zhiguo Wen, 2023. "Effects of the Dietary Replacement of Soybean Oil with Rubber Seed Oil on the Growth Performance, Carcass Trait, and Status of Lipid Metabolism in Pekin Ducks," Agriculture, MDPI, vol. 13(9), pages 1-12, August.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45520-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.