Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet.
Aberrant DNA methylation contributes to the abnormality of hepatic gene expression, one of the main factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Betaine is a methyl donor and has been considered to be a lipotropic agent. However, whether betaine supplementation improves NAFLD via its effect on the DNA methylation of specific genes and the genome has not been explored. Male C57BL/6 mice were fed either a control diet or high-fat diet (HFD) supplemented with 0%, 1% and 2% betaine in water (wt/vol) for 12 weeks. Betaine supplementation ameliorated HFD-induced hepatic steatosis in a dose-dependent manner. HFD up-regulated FAS and ACOX messenger RNA (mRNA) expression and down-regulated PPARα, ApoB and MTTP mRNA expression; however, these alterations were reversed by betaine supplementation, except ApoB. MTTP mRNA expression was negatively correlated with the DNA methylation of its CpG sites at -184, -156, -63 and -60. Methylation of these CpG sites was lower in both the 1% and 2% betaine-supplemented groups than in the HFD group (averages; 25.55% and 14.33% vs. 30.13%). In addition, both 1% and 2% betaine supplementation significantly restored the methylation capacity [S-adenosylmethionine (SAM) concentration and SAM/S-adenosylhomocysteine ratios] and genomic methylation level, which had been decreased by HFD (0.37% and 0.47% vs. 0.25%). These results suggest that the regulation of aberrant DNA methylation by betaine might be a possible mechanism of the improvements in NAFLD upon betaine supplementation.
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Li-jun
LJ
Wang
Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, University of Sun Yat-Sen, 510120 Guangzhou, People's Republic of China.
Hong-wei
HW
Zhang
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Jing-ya
JY
Zhou
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Yan
Y
Liu
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Yang
Y
Yang
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Xiao-ling
XL
Chen
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Cui-hong
CH
Zhu
Research and Therapy Center for Liver Disease, the Affiliated Dongnan Hospital of Xiamen University, 363000 Zhangzhou, People's Republic of China.
Rui-dan
RD
Zheng
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China.
Wen-hua
WH
Ling
Faculty of Nutrition, School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, People's Republic of China. Electronic address: zhuhl@mail.sysu.edu.cn.
Hui-lian
HL
Zhu
D000818:Animals; D001622:Betaine / Q000008:administration & dosage / Q000494:pharmacology*; D019175:DNA Methylation; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D013942:Thymine Nucleotides / Q000235:genetics*
D013942:Thymine Nucleotides; D001622:Betaine; C038567:O(4)-methylthymidine triphosphate
Betaine; DNA methylation; Methylation capacity; Microsomal triglyceride transfer protein; Nonalcoholic fatty liver disease