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Research Paper|Volume 15, Issue 12|pp 5550—5568

Mettl3-mediated m6A modification plays a role in lipid metabolism disorders and progressive liver damage in mice by regulating lipid metabolism-related gene expression

Guanqi Dai1,6, Shihao Huang1, Yonglong Li1,2, Xueyi Tu1, Jiawei Xia3, Zhihao Zhou1, Wanyi Chen1, Ao Zhang1, Jintao Lin1, Yingchun Li1, Danhua He1, Taoyan Lin4, Jinge Cong1,2, Ye Lei1,2, Liuxin Han3, Zhenxia Yao1, Weiwei Liu1, Ying Zhou1, Qiwen Li1, Jing Li5, Yuqin Zhang6, Aibing Wu7, Dong Xiao1,2, Wanshan Wang2, Wentao Zhao1,8, Junshuang Jia1, Xiaolin Lin9
  • 1Cancer Research Institute, Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
  • 2Laboratory Animal Management Center, Southern Medical University, Guangzhou 510515, China
  • 3The Third People’s Hospital of Kunming (The Sixth Affiliated Hospital of Dali University), Kunming 650041, China
  • 4Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  • 5Radiotherapy Center, The First People's Hospital of Chenzhou, Xiangnan University, Chenzhou 423000, China
  • 6Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
  • 7Department of Oncology, The Central People's Hospital of Zhanjiang, Zhanjiang 524000, China
  • 8Department of Gastrointestinal Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital, Yunnan Cancer Center), Kunming 650118, China
  • 9Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
* Equal contribution
Received: February 23, 2023Accepted: May 23, 2023Published: June 16, 2023

Copyright: © 2023 Dai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aims: N6-methyladenosine (m6A), the most abundant and conserved epigenetic modification of mRNA, participates in various physiological and pathological processes. However, the roles of m6A modification in liver lipid metabolism have yet to be understood entirely. We aimed to investigate the roles of the m6A “writer” protein methyltransferase-like 3 (Mettl3) in liver lipid metabolism and the underlying mechanisms.

Main Methods: We assessed the expression of Mettl3 in liver tissues of diabetes (db/db) mice, obese (ob/ob) mice, high saturated fat-, cholesterol-, and fructose-induced non-alcoholic fatty liver disease (NAFLD) mice, and alcohol abuse and alcoholism (NIAAA) mice by quantitative reverse-transcriptase PCR (qRT-PCR). Hepatocyte-specific Mettl3 knockout mice were used to evaluate the effects of Mettl3 deficiency in mouse liver. The molecular mechanisms underlying the roles of Mettl3 deletion in liver lipid metabolism were explored by multi-omics joint analysis of public data from the Gene Expression Omnibus database and further validated by qRT-PCR and Western blot.

Key Findings: Significantly decreased Mettl3 expression was associated with NAFLD progression. Hepatocyte-specific knockout of Mettl3 resulted in significant lipid accumulation in the liver, increased serum total cholesterol levels, and progressive liver damage in mice. Mechanistically, loss of Mettl3 significantly downregulated the expression levels of multiple m6A-modified mRNAs related to lipid metabolism, including Adh7, Cpt1a, and Cyp7a1, further promoting lipid metabolism disorders and liver injury in mice.

Significance: In summary, our findings demonstrate that the expression alteration of genes related to lipid metabolism by Mettl3-mediated m6A modification contributes to the development of NAFLD.