期刊
GENES & DISEASES
卷 9, 期 1, 页码 51-61出版社
ELSEVIER
DOI: 10.1016/j.gendis.2021.01.005
关键词
Adipose tissue; FTO; Lipid disorder diseases; Lipid metabolism; Liver; Skeletal muscle
资金
- National Natural Science Foundation of China [81770460]
- Natural Science Foundation of Guangxi Zhuang Autonomous Region, China [2019JJA140728]
- Natural Science Foundation of Hunan Province, China [2020JJ4532]
- Scientific Research Foundation for the Excellent Youth of the Education Department of Hunan province, China [18B264]
- Aid Program from the Science and Technology Bureau of Hengyang City, China [2017KJ268]
- Key Lab for Clinical Anatomy & Reproductive Medicine, China from the Science and Technology Bureau of Hengyang City, China [2017KJ182]
FTO mediates m(6)A demethylation to modulate lipid metabolism by affecting gene expression, leading to alterations in lipid synthesis, storage, and utilization.
The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated demethylation of m(6)A modification. FTO catalyzes the demethylation of m(6)A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1-mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBP beta pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPAR gamma and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPAR beta/delta and AMPK pathways by FTO-mediated m(6)A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m(6)A demethylation by FTO inhibits macrophage lipid influx by downregulating PPAR gamma protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m(6)A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases. Copyright (C) 2021, Chongqing Medical University. Production and hosting by Elsevier B.V.
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