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Dysregulated m6A Modification Promotes Lipogenesis and Development of Non-alcoholic Fatty Liver Disease and Hepatocellular Carcinoma.

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机构: [1]Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China [2]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 [3]Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, 450003, Zhengzhou, Henan, China [4]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 [6]Department of Hepatobiliary & Pancreatic Center, Chinese Academy of Medical Sciences and Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan,610072, China [7]Department of Urology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China [8]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 [9]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
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关键词: METTL14 SCD1 ACLY Lipid metabolism Type 2 diabetes mellitus

摘要:
Type 2 diabetes mellitus (DM2) is associated closely with Non-alcoholic fatty liver disease (NAFLD) through 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 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 MeRIP-qPCR analysis, we found that enhanced expression of ACLY and SCD1 in this NAFLD model and human HCC samples were 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 bind to mRNA of ACLY and SCD1 and alter their expression pattern. Our findings demonstrate a new NAFLD mouse model, which provide a study platform for DM2-related NAFLD; and reveal a unique epitranscriptional regulating mechanism for lipid metabolism via m6A-modified protein expression of ACLY and SCD1.Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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出版当年[2022]版:
大类 | 1 区 医学
小类 | 1 区 遗传学 1 区 生物工程与应用微生物 1 区 医学:研究与实验
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 生物工程与应用微生物 1 区 遗传学 1 区 医学:研究与实验
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出版当年[2022]版:
Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Q1 GENETICS & HEREDITY Q1 MEDICINE, RESEARCH & EXPERIMENTAL
最新[2023]版:
Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Q1 GENETICS & HEREDITY Q1 MEDICINE, RESEARCH & EXPERIMENTAL

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第一作者机构: [1]Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China [2]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 [3]Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, 450003, Zhengzhou, Henan, China [4]School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China
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通讯机构: [1]Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China [2]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 [3]Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, 450003, Zhengzhou, Henan, China [4]School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China [7]Department of Urology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072, China [8]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 [9]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 [*1]Shahe Campus of UESTC, No.4, Section 2, North Jianshe Road, Chenghua District, Chengdu, China, Postal Code: 610054
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