Enhanced hepatic cholesterol accumulation induced by maternal betaine exposure is associated with hypermethylation of CYP7A1 gene promoter.

Betaine contains three methyl groups and plays a critical role in regulating glucose and lipid metabolism via epigenetic modifications. However, it is unclear whether prenatal betaine intake could affect cholesterol metabolism of progeny through DNA methylation. Hence, pregnant rats were randomly divided into control and betaine groups fed standard diet or 1% betaine supplementation diet, respectively, throughout gestation and lactation. Maternal betaine exposure significantly (P < 0.05) increased serum and hepatic cholesterol contents but not triglyceride levels in offspring rats. Accordantly, maternal intake of betaine markedly downregulated (P < 0.05) hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) expression at both the mRNA and protein level, while the protein content of low-density lipoprotein receptor (LDLR) was upregulated in the liver of betaine-exposed rats. In addition, prenatal betaine supplementation extremely increased (P < 0.05) hepatic betaine-homocysteine methyltransferase (BHMT) expression at the mRNA and protein level but not affected the expression of other key enzymes involved in methionine metabolism. Furthermore, hepatic hypermethylation of CYP7A1 gene promoter was observed in progeny rats derived from betaine-supplemented dams. Our results provide evidence that maternal betaine supplementation significantly enhances hepatic cholesterol contents accompanied with alterations of cholesterol metabolic genes and hypermethylation in offspring rats at weaning.