Betaine Supplementation in Maternal Diet Modulates the Epigenetic Regulation of Hepatic Gluconeogenic Genes in Neonatal Piglets

Abstract

In this study, gestational sows were fed control or betaine-supplemented diets (3 g/kg) throughout the pregnancy, and the newborn piglets were used to elucidate whether maternal dietary betaine affected offspring hepatic gluconeogenic genes through epigenetic mechanisms. Neonatal piglets born to betaine-supplemented sows had significantly higher serum and hepatic betaine contents, together with significantly greater expression of methionine metabolic enzymes in the liver. Interestingly, significantly higher serum concentrations of lactic acid and glucogenic amino acids, including serine, glutamate, methionine and histidine, were detected in the piglets born to betaine-supplemented sows, which were coincident with higher hepatic glycogen content and PEPCK1 enzyme activity, as well as greater protein expression of gluconeogenic enzymes, pyruvate carboxylase (PC), cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK1), mitochondrional phosphoenolpyruvate carboxykinase (PEPCK2) and fructose-1, 6-bisphosphatase (FBP1). Moreover, maternal betaine significantly changed the methylation status of both CpGs and histones on the promoter of gluconeogenic genes. The lower PEPCK1 mRNA was associated with DNA hypermethylation and more enriched repression histone mark H3K27me3, while the up-regulated PEPCK2 and FBP1 mRNA was associated with DNA hypomethylation and more enriched activation histone mark H3K4me3. Furthermore, the expression of two miRNAs predicted to target PC and 6 miRNAs predicted to target PEPCK1 was dramatically suppressed in the liver of piglets born to betaine-supplemented sows. Our results provide the first evidence that maternal betaine supplementation affects hepatic gluconeogenic genes expression in newborn piglets through enhanced hepatic methionine metabolism and epigenetic regulations, which involve DNA and histone methylations, and possibly miRNAs-mediated post-transcriptional mechanism.

Maternal Betaine Supplementation throughout Gestation and Lactation Modifies Hepatic Cholesterol Metabolic Genes in Weaning Piglets via AMPK/LXR-Mediated Pathway and Histone Modification

“…However, we found more enrichment of histone-activated marker H3K4me3 on the LDLR and SR-BI genes’ promoters, which is associated with enhanced gene transcription. It is noted that H3K4me3 is trimethylated by a SAM-dependent enzyme, SETD7 [40], and our previous study has demonstrated that maternal betaine diet increases SETD7 expression in the liver of offspring [41]. Therefore, in the present study, enhanced SAM content may greatly contribute to activate histone modification in the promoters of hepatic cholesterol metabolic genes in the betaine-exposed weaning piglets.…”

Maternal betaine supplementation in rats induces intergenerational changes in hepatic IGF‐1 expression and DNA methylation

“…Methylated DNA immunoprecipitation analysis was performed as previously described . Purified genomic DNA from liver tissue was fragmented to a mean size of 300 base pairs (bp).…”

“…Betaine is critical for embryonic and fetal development . Maternal betaine supplementation during gestation affects hepatic expression of gluconeogenic and lipogenic genes in neonatal piglets, which involves modifications of DNA methylation on the promoter of affected genes.…”

Changes in milk performance and hepatic metabolism in mid-lactating dairy goats after being fed a high concentrate diet for 10 weeks

“…Hepatic PEPCK1 enzyme activity was detected as previously described (Cai et al, 2014). In brief, 0.5 g of liver tissue was homogenized in a lysis buffer (0.25 M sucrose and 5 mM Tris-HCl, pH 7.4) at 4°C.…”