Epigenetic Regulation of Key Enzymes CYP7a1 and HMGCR Affect Hepatic Cholesterol Metabolism in Different Breeds of Piglets.

Xian Li,Rihua Cong,Xiaoqian Jian,Xiangyin Zhang,Hui Zhang,Yang Mu,Hua Wang,Hanyang Xiao,Shulin Chen

doi:10.3389/fvets.2020.00231

Xian Li, Rihua Cong + Show 7 more

Open Access

https://doi.org/10.3389/fvets.2020.00231

Copy DOI

Abstract

Liver is the place where cholesterol is synthesized, transported, secreted, and transformed, thus liver takes an irreplaceable role in cholesterol homeostasis. Hepatic cholesterol metabolism differs between breeds, yet the molecular mechanism is unclear. In this study Large White (LW) and Erhualian (EHL) piglets (at birth and 25-day-old) were used, 6 each time point per breed. Erhualian piglets had significantly lower body and liver weight compared with Large White at birth and weaning, but the liver/ body weight ratio was higher at weaning, associated with increased serum and liver cholesterol and triglyceride content. The mRNA expression of Cholesterol-7alpha-hydroxylase (CYP7a1) and Recombinant Acetyl Coenzyme Acetyltransferase 2 (ACAT2) were down-regulated in Erhualian piglets at birth, while hepatic Sterol-regulatory element binding protein 2 (SREBP2) mRNA expression was up-regulated in Erhualian piglets at weaning, as well as SREBP2 protein content, compared with Large White piglets. At birth, the depressed CYP7a1 transcription in Erhualian piglets was associated with decreased Histone H3 (H3) and increased Histone H3 lysine 27 trimethylation (H3K27me3). While the results revealed significant promoter hypermethylation of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) promoter in Erhualian piglets at weaning, together with increased Histone H3 lysine 9 monomethylation (H3K9me1) and Histone H3 lysine 4 trimethylation (H3K4me3). These results suggest that epigenetic modification may be an important mechanism in hepatic cholesterol metabolism among different species, which is vital for maintaining cholesterol homeostasis and decreasing risk of cardiovascular disease.

Highlights

Cholesterol participates in the formation of cell membrane [1] and can synthesis bile acid and vitamin D as a precursor, which is of great significance to the life activities of the body [2, 3]
Low-density lipoprotein (LDL) molecules are the main operator of cholesterol in the blood which are responsible for transporting liver cholesterol to other peripheral tissues, while High-density lipoprotein (HDL) transports cholesterol from extrahepatic tissues back to the liver
We have presented evidences that serum concentration and liver content of total cholesterol (Tch) and High-density lipoprotein cholesterol (HDL-C) were higher in EHL piglets, which was in agreement with early findings

Summary

BACKGROUND

Cholesterol participates in the formation of cell membrane [1] and can synthesis bile acid and vitamin D as a precursor, which is of great significance to the life activities of the body [2, 3]. Polymorphisms at genetic loci may be associated with significant heterogeneity in sensitivity to dietary cholesterol These polymorphisms include absorption of dietary cholesterol, conversion of liver cholesterol to bile acids, feedback inhibition of endogenous cholesterol synthesis, or regulation of the LDL-R pathway [13,14,15]. In angiocardiopathy and cancer researches, CYP7a1 and HMGCR gene are described to be vulnerable to epigenetic regulation including DNA methylation and histone modification [18]. The activation of HMGCR transcription is accompanied by an increase in H3 acetylation and a decrease in histones H3, H3K9me, and H3K27me3 [21,22,23,24] Based on these studies, we hypothesized that epigenetic events have a crucial function in modifying liver cholesterol metabolism in Large White and Erhualian piglets

MATERIALS AND METHODS

F: TACATGGTCTACATGTTC

RESULT

Findings

DISCUSSION