Molecular Mechanism of Metabolic Memory via a DNA Methylation and Its Medical Application

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In this study, we analyzed epigenetic regulation of lipid metabolism in mouse liver in perinatal periods. In neonatal periods, DNA methylation of de novo lipogenic glycerol-3-phosphate acyltransferase 1 (GPAT1) gene (Gpam) promoter suppresses the gene expression, whereas Gpam expression is induced in the weaning period via a DNA demethylation mechanism. This suggests de novo mouse hepatic lipogenesis in perinatal periods is regulated by DNA methylation. We also analyzed DNA methylation in neonatal mouse liver from the birth to weaning. It revealed that fatty acid beta-oxidation enzymes were highlighted among the genes, which showed DNA demethylation and increased gene expression in postnatal periods. We also demonstrated that the DNA demethylation is peroxisome proliferator-activated receptor (PPAR)-alpha dependent. This study shed a light on the importance of intrinsic lipid ligands in milk in the epigenetic regulation of lipid metabolism in perinatal mouse liver.