The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression

doi:10.1038/s41467-021-27539-3

	The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression
	Li, Xinzhi 1; Yuan, Bingchuan 1; Lu, Min 1; Wang, Yuqin 1; Ding, Na 1; Liu, Chunhong 1; Gao, Ming 1; Yao, Zhicheng 2; Zhang, Shiyan 3,4; Zhao, Yujun 3,4
刊名	NATURE COMMUNICATIONS
	2021-12-10
卷号	12 期号:1 页码:17
DOI	10.1038/s41467-021-27539-3
通讯作者	Chen, Zheng(chenzheng@hit.edu.cn)
英文摘要	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. Mechanisms that underlie the progression of non-alcoholic fatty liver disease to the more severe non-alcoholic steatohepatitis are incompletely understood. Here the authors show that METTL3, a RNA methyltransferase that catalyzes mRNA m6 modifications, negatively regulates NASH progression via inhibiting the transcription of Cd36 and Ccl2.
资助项目	National Natural Science Foundation of China[92057110] ; National Natural Science Foundation of China[31971083] ; Natural Science Foundation of Heilongjiang Province[YQ2019C011] ; Chinese Postdoctoral Science Foundation[AUGA4130900619]
WOS关键词	FATTY LIVER-DISEASE ; B-INDUCING KINASE ; RNA ; N-6-METHYLADENOSINE ; PHOSPHORYLATION ; PATHOGENESIS ; INFLAMMATION ; EXPRESSION ; CHROMATIN ; PROTEINS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PORTFOLIO
WOS记录号	WOS:000729179400041
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/299193]
专题	中国科学院上海药物研究所
通讯作者	Chen, Zheng
作者单位	1.Harbin Inst Technol, Sch Life Sci & Technol, HIT Ctr Life Sci, Harbin 150001, Peoples R China 2.Sun Yat Sen Univ, Dept Gen Surg, Affiliated Hosp 3, Guangzhou 510530, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Guangdong Acad Sci, State Key Lab Appl Microbiol Southern China, Guangdong Prov Key Lab Microbial Culture Collect, Guangdong Open Lab Appl Microbiol,Inst Microbiol, Guangzhou 510070, Peoples R China
推荐引用方式 GB/T 7714	Li, Xinzhi,Yuan, Bingchuan,Lu, Min,et al. The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression[J]. NATURE COMMUNICATIONS,2021,12(1):17.
APA	Li, Xinzhi.,Yuan, Bingchuan.,Lu, Min.,Wang, Yuqin.,Ding, Na.,...&Chen, Zheng.(2021).The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression.NATURE COMMUNICATIONS,12(1),17.
MLA	Li, Xinzhi,et al."The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression".NATURE COMMUNICATIONS 12.1(2021):17.