m6A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

Yuhuan Li; Qingyang Zhang; Guanshen Cui; Fang Zhao; Xin Tian; Bao-Fa Sun; Ying Yang; Wei Li

doi:10.1016/j.gpb.2020.06.003

m⁶A Regulates Liver Metabolic Disorders and Hepatogenous Diabetes

Genomics Proteomics Bioinformatics. 2020 Aug;18(4):371-383. doi: 10.1016/j.gpb.2020.06.003. Epub 2020 Nov 5.

Authors

Yuhuan Li¹, Qingyang Zhang², Guanshen Cui², Fang Zhao³, Xin Tian³, Bao-Fa Sun⁴, Ying Yang⁵, Wei Li⁶

Affiliations

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100101, China.
² University of Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; China National Center for Bioinformation, Beijing 100101, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China.
³ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
⁴ University of Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; China National Center for Bioinformation, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
⁵ University of Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, College of Future Technology, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; China National Center for Bioinformation, Beijing 100101, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 101408, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: yingyang@big.ac.cn.
⁶ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: liwei@ioz.ac.cn.

Abstract

N⁶-methyladenosine (m⁶A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m⁶A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m⁶A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m⁶A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m⁶A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated m⁶A in HFD-induced metabolic disorders and hepatogenous diabetes.

Keywords: High fat diet; Insulin resistance; Lpin1; Mettl3; RNA methylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine
Animals
Diabetes Mellitus* / genetics
Liver
Methyltransferases* / genetics
Mice
RNA, Messenger

Substances

RNA, Messenger
Methyltransferases
Adenosine