title: FTO-dependent function of N6-methyladenosine is involved in the hepatoprotective effects of betaine on adolescent mice.
abstract: Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease among children and adolescents in the developed world. Betaine, as a methyl donor, recently has been demonstrated to exert its hepatoprotective effects through rectifying the genomic DNA hypomethylation state. However, whether betaine supplementation affects N6-methyladenosine (m(6)A) mRNA methylation in NAFLD is still unknown. We conducted the current study to investigate the effects of betaine supplementation during adolescence on high-fat diet-induced pathological changes in liver of mice, and we further identified the effects of betaine supplementation on expression of the fat mass and obesity-associated gene (FTO) and hepatic m(6)A mRNA methylation. Our results showed that betaine supplementation across adolescence significantly alleviated high-fat-induced impairment of liver function and morphology as well as ectopic fat accumulation. Surprisingly, no significant effects on serum TG and NEFA level, as well as fat mass, were observed in mice supplemented with betaine. We also found that high-fat diet upregulated ACC1 and FAS gene expression and downregulated HSL and ATGL gene expression. However, these alterations were rectified by betaine supplementation. Moreover, an m(6)A hypomethylation state and increased FTO expression were detected in mice fed with high-fat diet, while betaine supplementation prevented these changes. Our results suggested that betaine supplementation during adolescence could protect mice from high-fat-induced NAFLD by decreasing de novo lipogenesis and increasing lipolysis. Furthermore, a novel FTO-dependent function of m(6)A may involve in the hepatoprotective effects of betaine.
authors.affiliation: Key Laboratory of Animal Nutrition and Feed Science, Ministry of Agriculture, Zhejiang Provincial Laboratory of Feed and Animal Nutrition, Institute of Feed Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang Province, 310058, People's Republic of China.
authors.forename: Jingqing
authors.initials: J
authors.lastname: Chen
authors.forename: Xihong
authors.initials: X
authors.lastname: Zhou
authors.forename: Weiche
authors.initials: W
authors.lastname: Wu
authors.forename: Xinxia
authors.initials: X
authors.lastname: Wang
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D001622:Betaine / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood; D019610:Cytoprotection; D059305:Diet, High-Fat / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008745:Methylation; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000502:physiology*; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology; D007652:Oxo-Acid-Lyases / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D001622:Betaine; D002784:Cholesterol; C010223:N-methyladenosine; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases; D000241:Adenosine