Maternal low-protein diet causes epigenetic deregulation of HMGCR and CYP7α1 in the liver of weaning piglets

To investigate the effect of maternal dietary protein on hepatic cholesterol metabolism in offspring pigs and to detect underlying epigenetic mechanisms, 14 primiparous purebred Meishan sows were fed standard-protein (SP, n=7) or low-protein (LP, 50% of SP, n=7) diets during pregnancy and lactation, respectively. LP piglets showed significantly lower body weight and liver weight at weaning, associated with decreased liver and serum cholesterol content. Hepatic SREBP2, HMGCR and CYP7α1 mRNA expressions were all up-regulated in LP piglets, as well as SREBP2 protein content and HMGCR enzyme activity, compared to SP piglets, while the mRNA expression of LDLR, FXR, LXR and CYP27α1 was not altered. Hepatic activation of HMGCR gene transcription in LP piglets was associated with promoter hypomethylation, together with decreased histone H3, H3 lysine 9 monomethylation (H3K9me1) and H3 lysine 27 trimethylation (H3K27me3) and increased H3 acetylation. No CpG islands were predicted in the CYP7α1 promoter, and the augmented CYP7α1 transcription in LP piglets was associated with decreased H3, H3K9me1 and H3K27me3. No alterations were detected for hepatic expression of microRNAs predicted to target 3′-UTR of HMGCR or CYP7α1 gene. These results indicate that maternal low-protein diet during gestation and lactation affects hepatic cholesterol metabolism in weaning piglets by modifying the epigenetic regulation of HMGCR and CYP7α1 genes, which implicates possible long-term consequences in cholesterol homeostasis later in adult life.