Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet
Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet
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DOI：
10.1016/j.jnutbio.2013.11.007
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发表时间：
2014-03-01
影响因子：
5.6
通讯作者：
Zhu, Hui-lian
中科院分区：
文献类型：
--
作者：
Wang, Li-jun;Zhang, Hong-wei;Zhu, Hui-lian
DNA甲基化异常导致肝脏基因表达异常，是非酒精性脂肪性肝病（NAFLD）发病的主要因素之一。甜菜碱是一种甲基供体，被认为是一种抗脂肪酸剂。然而，甜菜碱补充剂是否通过其对特定基因和基因组的DNA甲基化的影响来改善NAFLD尚未被探索。雄性C57 BL/6小鼠喂食对照饮食或补充有0%、1%和2%甜菜碱水溶液（wt/vol）的高脂肪饮食（HFD）12周。补充甜菜碱以剂量依赖性方式改善HFD诱导的肝脂肪变性。HFD上调FAS和ACOX信使RNA（mRNA）表达，下调PPAR α，ApoB和MTTP mRNA表达;然而，这些变化被甜菜碱补充逆转，ApoB除外。MTTP mRNA表达与其CpG位点-184、-156、-63和-60的DNA甲基化呈负相关。这些CpG位点的甲基化在1%和2%甜菜碱补充组中均低于HFD组（平均值; 25.55%和14.33%对30.13%）。此外，1%和2%甜菜碱补充显著恢复了甲基化能力[S-腺苷甲硫氨酸（SAM）浓度和SAM/S-腺苷高半胱氨酸比率]和基因组甲基化水平，HFD降低了甲基化能力和基因组甲基化水平（0.37%和0.47% vs. 0.25%）。这些结果表明，甜菜碱对DNA异常甲基化的调节可能是甜菜碱改善NAFLD的可能机制。(C)2014爱思唯尔公司All rights reserved.
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 PPAR alpha, 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. (C) 2014 Elsevier Inc. All rights reserved.