Role of DNA methylation in the regulation of lipogenic glycerol-3-phosphate acyltransferase 1 gene expression in the mouse neonatal liver.
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.
Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Tatsuya
T
Ehara
Yasutomi
Y
Kamei
Mayumi
M
Takahashi
Xunmei
X
Yuan
Sayaka
S
Kanai
Erina
E
Tamura
Miyako
M
Tanaka
Tomomi
T
Yamazaki
Shinji
S
Miura
Osamu
O
Ezaki
Takayoshi
T
Suganami
Masaki
M
Okano
Yoshihiro
Y
Ogawa
D016475:3T3 Cells; D000818:Animals; D000831:Animals, Newborn; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005786:Gene Expression Regulation; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
D002843:Chromatin; D004248:DNA (Cytosine-5-)-Methyltransferases; D005992:Glycerol-3-Phosphate O-Acyltransferase; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D000097584:DNA Methyltransferase 3B