IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38371-2.html
   My bibliography  Save this article

UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis

Author

Listed:
  • Tao Zhang

    (Huazhong University of Science and Technology
    Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences
    Boston Children’s Hospital, Harvard Medical School)

  • Na Zhang

    (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jing Xing

    (Lingang Laboratory)

  • Shuhua Zhang

    (Huazhong University of Science and Technology
    Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences)

  • Yulu Chen

    (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

  • Daichao Xu

    (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
    Shanghai Key Laboratory of Aging Studies
    Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

  • Jinyang Gu

    (Huazhong University of Science and Technology
    Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences
    Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

Abstract

Hepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. UGDH is progressively reduced in proportion to NASH severity. UGDH absence from hepatocytes hastens the development of liver damage in male mice with NASH, which is suppressed by RIPK1 kinase-dead knockin mutation. Mechanistically, UGDH suppresses RIPK1 by converting UDP-glucose to UDP-glucuronate, the latter directly binds to the kinase domain of RIPK1 and inhibits its activation. Recovering UDP-glucuronate levels, even after the onset of NASH, improved liver damage. Our findings reveal a role for UGDH and UDP-glucuronate in NASH pathogenesis and uncover a mechanism by which UDP-glucuronate controls hepatocyte apoptosis by targeting RIPK1 kinase, and suggest UDP-glucuronate metabolism as a feasible target for more specific treatment of NASH-associated liver damage.

Suggested Citation

  • Tao Zhang & Na Zhang & Jing Xing & Shuhua Zhang & Yulu Chen & Daichao Xu & Jinyang Gu, 2023. "UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38371-2
    DOI: 10.1038/s41467-023-38371-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38371-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-38371-2?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. Holger Hengel & Célia Bosso-Lefèvre & George Grady & Emmanuelle Szenker-Ravi & Hankun Li & Sarah Pierce & Élise Lebigot & Thong-Teck Tan & Michelle Y. Eio & Gunaseelan Narayanan & Kagistia Hana Utami , 2020. "Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    2. Xiongjun Wang & Ruilong Liu & Wencheng Zhu & Huiying Chu & Hua Yu & Ping Wei & Xueyuan Wu & Hongwen Zhu & Hong Gao & Ji Liang & Guohui Li & Weiwei Yang, 2019. "UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis," Nature, Nature, vol. 571(7763), pages 127-131, July.
    3. Jiefei Geng & Yasushi Ito & Linyu Shi & Palak Amin & Jiachen Chu & Amanda Tomie Ouchida & Adnan Kasim Mookhtiar & Heng Zhao & Daichao Xu & Bing Shan & Ayaz Najafov & Guangping Gao & Shizuo Akira & Jun, 2017. "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    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. Hailin Tu & Weihang Xiong & Jie Zhang & Xueqiang Zhao & Xin Lin, 2022. "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Jingchun Du & Yougui Xiang & Hua Liu & Shuzhen Liu & Ashwani Kumar & Chao Xing & Zhigao Wang, 2021. "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Weiqiang Lu & Jiayan Cui & Wanyan Wang & Qian Hu & Yun Xue & Xi Liu & Ting Gong & Yiping Lu & Hui Ma & Xinyu Yang & Bo Feng & Qi Wang & Naixia Zhang & Yechun Xu & Mingyao Liu & Ruth Nussinov & Feixion, 2024. "PPIA dictates NRF2 stability to promote lung cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Lingjie Yan & Tao Zhang & Kai Wang & Zezhao Chen & Yuanxin Yang & Bing Shan & Qi Sun & Mengmeng Zhang & Yichi Zhang & Yedan Zhong & Nan Liu & Jinyang Gu & Daichao Xu, 2022. "SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Jiang Zhu & Kang Chen & Yu H. Sun & Wen Ye & Juntao Liu & Dandan Zhang & Nan Su & Li Wu & Xiaochen Kou & Yanhong Zhao & Hong Wang & Shaorong Gao & Lan Kang, 2023. "LSM1-mediated Major Satellite RNA decay is required for nonequilibrium histone H3.3 incorporation into parental pronuclei," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    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:14:y:2023:i:1:d:10.1038_s41467-023-38371-2. 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.