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The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression

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  • Xinzhi Li

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Bingchuan Yuan

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Min Lu

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Yuqin Wang

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Na Ding

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Chunhong Liu

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Ming Gao

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

  • Zhicheng Yao

    (The third affiliated hospital of Sun Yat-sen university)

  • Shiyan Zhang

    (State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yujun Zhao

    (State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Liwei Xie

    (Guangdong Academy of Sciences)

  • Zheng Chen

    (HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology)

Abstract

Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of Mettl3 drives NAFL-to-NASH progression by increasing CD36-mediated hepatic free fatty acid uptake and CCL2-induced inflammation, which is due to increased chromatin accessibility in the promoter region of Cd36 and Ccl2. Antibody blockade of CD36 and CCL2 ameliorates NASH progression in hepatic Mettl3 knockout mice. Hepatic overexpression of Mettl3 protects against NASH progression by inhibiting the expression of CD36 and CCL2. Mechanistically, METTL3 directly binds to the promoters of the Cd36 and Ccl2 genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing Cd36 and Ccl2 transcription. Furthermore, METTL3 is translocated from the nucleus to the cytosol in NASH, which is associated with CDK9-mediated phosphorylation of METTL3. Our data reveal a mechanism by which METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against NASH progression.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27539-3
    DOI: 10.1038/s41467-021-27539-3
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    1. Isaia Barbieri & Konstantinos Tzelepis & Luca Pandolfini & Junwei Shi & Gonzalo Millán-Zambrano & Samuel C. Robson & Demetrios Aspris & Valentina Migliori & Andrew J. Bannister & Namshik Han & Etienne, 2017. "Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control," Nature, Nature, vol. 552(7683), pages 126-131, December.
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    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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    1. 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.

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