The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression

Xinzhi Li, Bingchuan Yuan, Min Lu, Yuqin Wang, Na Ding, Chunhong Liu, Ming Gao, Zhicheng Yao, Shiyan Zhang, Yujun Zhao, Liwei Xie and Zheng Chen ()
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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
Yujun Zhao: State Key Laboratory of Drug Research and Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, 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

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27539-3

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