Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Diabetes. 2012 Oct;61(10):2442-50. doi: 10.2337/db11-1834. Epub 2012 Jun 20.
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.
肝脏是脂质代谢的主要器官，其会明显响应生理营养需求而发生改变；然而，人们对于生命早期肝脏中脂肪生成基因表达的调控知之甚少。在这项研究中，我们表明甘油-3-磷酸酰基转移酶 1（GPAT1；Gpam）的表达受到 DNA 甲基化的调控，该酶是甘油三酯生物合成的限速酶，DNA 甲基化是一种参与调控哺乳动物多种生物过程的表观遗传修饰。在新生鼠肝脏中，Dnmt3b 可能诱导 Gpam 启动子的 DNA 甲基化，从而抑制脂肪生成转录因子固醇调节元件结合蛋白-1c（SREBP-1c）的募集，而在成年肝脏中，DNA 甲基化减少导致活性染色质构象，从而允许 SREBP-1c 的募集。母体营养过剩导致幼鼠肝脏中 Gpam 启动子的甲基化减少，GPAT1 表达增加，甘油三酯含量增加，这表明营养等环境因素可以影响肝脏中的 DNA 甲基化。本研究首次对甘油三酯生物合成基因 Gpam 的 DNA 甲基化依赖性调控进行了详细分析，从而为代谢基因的表观遗传调控及其代谢性疾病的分子机制提供了新的见解。
