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Role of DNA Methylation in the Regulation of Lipogenic Glycerol-3-Phosphate Acyltransferase 1 Gene Expression in the Mouse Neonatal Liver

机译:DNA甲基化在小鼠新生肝脏中脂肪甘油3磷酸酰基转移酶1基因表达调控中的作用。

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摘要

The liver is a major organ of lipid metabolism, which is markedly changed in response to physiological nutritional demand; however, the regulation of hepatic lipogenic gene expression in early life is largely unknown. In this study, we show that expression of glycerol-3-phosphate acyltransferase 1 (GPAT1; Gpam), a rate-limiting enzyme of triglyceride biosynthesis, is regulated in the mouse liver by DNA methylation, an epigenetic modification involved in the regulation of a diverse range of biological processes in mammals. In the neonatal liver, DNA methylation of the Gpam promoter, which is likely to be induced by Dnmt3b, inhibited recruitment of the lipogenic transcription factor sterol regulatory element–binding protein-1c (SREBP-1c), whereas in the adult, decreased DNA methylation resulted in active chromatin conformation, allowing recruitment of SREBP-1c. Maternal overnutrition causes decreased Gpam promoter methylation with increased GPAT1 expression and triglyceride content in the pup liver, suggesting that environmental factors such as nutritional conditions can affect DNA methylation in the liver. This study is the first detailed analysis of the DNA-methylation–dependent regulation of the triglyceride biosynthesis gene Gpam, thereby providing new insight into the molecular mechanism underlying the epigenetic regulation of metabolic genes and thus metabolic diseases.
机译:肝脏是脂质代谢的主要器官,它会根据生理营养需求而发生明显变化。然而,在早期生命中肝脏脂肪生成基因表达的调控尚不清楚。在这项研究中,我们表明,甘油三酸酯生物合成的限速酶甘油3磷酸酰基转移酶1(GPAT1; Gpam)的表达在小鼠肝脏中受到DNA甲基化的调节,DNA甲基化是一种参与遗传调控a哺乳动物的各种生物过程。在新生儿肝脏中,可能由Dnmt3b诱导的Gpam启动子的DNA甲基化抑制了脂生性转录因子固醇调节元件结合蛋白1c(SREBP-1c)的募集,而在成年人中,DNA甲基化的降低导致活跃的染色质构象,从而允许SREBP-1c募集。母体营养不良会导致幼仔肝脏Gpam启动子甲基化减少,GPAT1表达增加,甘油三酯含量增加,这表明诸如营养条件之类的环境因素会影响肝脏DNA甲基化。这项研究是对甘油三酸酯生物合成基因Gpam依赖于DNA甲基化的调控的首次详细分析,从而提供了对代谢基因进而代谢疾病的表观遗传调控的分子机制的新见解。

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