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

Author

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  • 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
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    References listed on IDEAS

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    1. 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.
    2. 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.
    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.
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