Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma

Yeming Yang; Jingshu Cai; Xue Yang; Kaifang Wang; Kuanxiang Sun; Zhenglin Yang; Lin Zhang; Lu Yang; Chun Gu; Xiang Huang; Ziyan Wang; Xianjun Zhu

doi:10.1016/j.ymthe.2022.02.021

Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma

Mol Ther. 2022 Jun 1;30(6):2342-2353. doi: 10.1016/j.ymthe.2022.02.021. Epub 2022 Feb 19.

Authors

Yeming Yang¹, Jingshu Cai², Xue Yang², Kaifang Wang², Kuanxiang Sun³, Zhenglin Yang⁴, Lin Zhang⁴, Lu Yang², Chun Gu⁵, Xiang Huang⁶, Ziyan Wang⁷, Xianjun Zhu⁸

Affiliations

¹ Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
² School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
³ Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
⁴ The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
⁵ Department of Hepatobiliary & Pancreatic Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Department of Hepatobiliary & Pancreatic Center, Chinese Academy of Medical Sciences and Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan 610072, China.
⁶ Department of Urology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China. Electronic address: huangxiang@med.uestc.edu.cn.
⁷ Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China. Electronic address: ziyanwang@uestc.edu.cn.
⁸ Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China; Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072 China; Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Xining, Qinghai 810008, China. Electronic address: xjzhu@uestc.edu.cn.

Abstract

Type 2 diabetes mellitus (DM2) is associated closely with non-alcoholic fatty liver disease (NAFLD) by affecting lipid metabolism, which may lead to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). N⁶-methyladenosine (m6A) RNA methylation is an important epigenetic regulation for gene expression and is related to HCC development. We developed a new NAFLD model oriented from DM2 mouse, which spontaneously progressed to histological features of NASH, fibrosis, and HCC with high incidence. By RNA sequencing, protein expression and methylated RNA immunoprecipitation (MeRIP)-qPCR analysis, we found that enhanced expression of ACLY and SCD1 in this NAFLD model and human HCC samples was due to excessive m6A modification, but not elevation of mature SREBP1. Moreover, targeting METTL3/14 in vitro increases protein level of ACLY and SCD1 as well as triglyceride and cholesterol production and accumulation of lipid droplets. m6A sequencing analysis revealed that overexpressed METTL14 binds to mRNA of ACLY and SCD1 and alters their expression pattern. Our findings demonstrate a new NAFLD mouse model that provides a study platform for DM2-related NAFLD and reveals a unique epitranscriptional regulating mechanism for lipid metabolism via m6A-modified protein expression of ACLY and SCD1.

Keywords: ACLY; METTL14; SCD1; lipid metabolism; type 2 diabetes mellitus.

Publication types

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

MeSH terms

Animals
Carcinoma, Hepatocellular* / pathology
Diabetes Mellitus, Type 2* / genetics
Epigenesis, Genetic
Fibrosis
Lipogenesis / genetics
Liver Neoplasms* / metabolism
Mice
Non-alcoholic Fatty Liver Disease* / metabolism
RNA, Messenger / genetics

Substances

RNA, Messenger