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Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)

Author

Listed:
  • Xinzhi Li

    (Harbin Institute of Technology)

  • Kaixin Ding

    (Harbin Institute of Technology)

  • Xueying Li

    (Harbin Institute of Technology)

  • Bingchuan Yuan

    (Harbin Institute of Technology)

  • Yuqin Wang

    (Harbin Institute of Technology)

  • Zhicheng Yao

    (The Third Affiliated Hospital of Sun Yat-sen University)

  • Shuaikang Wang

    (Fudan University)

  • He Huang

    (Fudan University)

  • Bolin Xu

    (Peking University)

  • Liwei Xie

    (Guangdong Academy of Sciences)

  • Tuo Deng

    (The Second Xiangya Hospital of Central South University)

  • Xiao-wei Chen

    (Peking University)

  • Zheng Chen

    (Harbin Institute of Technology)

Abstract

Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g., Igfbp1, Cd36 and Ccl2) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression.

Suggested Citation

  • Xinzhi Li & Kaixin Ding & Xueying Li & Bingchuan Yuan & Yuqin Wang & Zhicheng Yao & Shuaikang Wang & He Huang & Bolin Xu & Liwei Xie & Tuo Deng & Xiao-wei Chen & Zheng Chen, 2022. "Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32163-w
    DOI: 10.1038/s41467-022-32163-w
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    References listed on IDEAS

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    1. Xinzhi Li & Bingchuan Yuan & Min Lu & Yuqin Wang & Na Ding & Chunhong Liu & Ming Gao & Zhicheng Yao & Shiyan Zhang & Yujun Zhao & Liwei Xie & Zheng Chen, 2021. "The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Eric L. Nostrand & Peter Freese & Gabriel A. Pratt & Xiaofeng Wang & Xintao Wei & Rui Xiao & Steven M. Blue & Jia-Yu Chen & Neal A. L. Cody & Daniel Dominguez & Sara Olson & Balaji Sundararaman & Liju, 2020. "A large-scale binding and functional map of human RNA-binding proteins," Nature, Nature, vol. 583(7818), pages 711-719, July.
    3. Yuqin Wang & Ming Gao & Fuxing Zhu & Xinzhi Li & Ying Yang & Qiuxin Yan & Linna Jia & Liwei Xie & Zheng Chen, 2020. "METTL3 is essential for postnatal development of brown adipose tissue and energy expenditure in mice," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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    Cited by:

    1. Zimeng Xin & Tianying Zhang & Qinyue Lu & Zhangping Yang & Zhi Chen, 2022. "Progress of m 6 A Methylation in Lipid Metabolism in Humans and Animals," Agriculture, MDPI, vol. 12(10), pages 1-18, October.

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