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

• Published in: Molecular therapy Vol. 30; no. 6; pp. 2342 - 2353
• Main Authors: Yang, Yeming, Cai, Jingshu, Yang, Xue, Wang, Kaifang, Sun, Kuanxiang, Yang, Zhenglin, Zhang, Lin, Yang, Lu, Gu, Chun, Huang, Xiang, Wang, Ziyan, Zhu, Xianjun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2022; American Society of Gene & Cell Therapy
• Subjects: ACLY; Animals; Carcinoma, Hepatocellular - pathology; Diabetes Mellitus, Type 2 - genetics; Epigenesis, Genetic; Fibrosis; lipid metabolism; Lipogenesis - genetics; Liver Neoplasms - metabolism; METTL14; Mice; Non-alcoholic Fatty Liver Disease - metabolism; Original; RNA, Messenger - genetics; SCD1; type 2 diabetes mellitus; type 2 diabetes mellitus; ACLY; METTL14; SCD1; lipid metabolism
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2022.02.021

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.
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The authors develop a new non-alcoholic fatty liver disease mouse model, which spontaneously progresses to hepatocellular carcinoma. They demonstrate that the enhanced lipid production is due to excessive m6A modification of ACLY and SCD1 by increased METTL3 and METTL14. This study reveals a unique epitranscriptional regulating mechanism for lipid metabolism.