Abstract
Obesity has been correlating with low levels of glutathione (GSH) and 25-hydroxyvitamin D3 (25(OH)VD3). The liver is the principal site for the 25(OH)VD3 biosynthesis. This study investigated whether GSH deficiency induces epigenetic alterations that impair Vitamin D (VD) metabolism genes in the livers of HFD-fed mice. The expression of the VD metabolism genes CYP2R1 and CYP27A1 (25-hydroxylase), CYP27B1 (1-α-hydroxylase), and vitamin D receptor (VDR) were downregulated in the livers of mice fed an HFD (GSH- deficient) compared with control diet-fed group. The expression of CYP24A1 (24-hydroxylase) was significantly increased, which catabolizes both 25(OH)VD3 and 1α,25-hydroxyvitaminD3. Gene-specific hypermethylation of 25-hydroxylase, 1-α-hydroxylase, and VDR, and hypomethylation of CYP24A1 was observed in HFD-fed mice. GSH deficiency induced in cultured hepatocytes caused an increase in oxidative stress and alterations in VD regulatory genes. Similarly, elevated global DNA methylation, Dnmt activity, and 5-methylcytosine but decreased Tet activity and 5-hydroxymethylcytosine were observed in the GSH-deficient hepatocytes and the liver of HFD-fed mice. Replenishment of GSH by its prodrugs treatment beneficially altered epigenetic enzymes, and VD-metabolism genes in hepatocytes. HFD-induces GSH deficiency and epigenetically alters VD-biosynthesis pathway genes. This provides a biochemical mechanism for the VD-deficiency and potential benefits of GSH treatment in reducing 25(OH)VD3-deficiency.
Highlights
Epigenetic regulation of gene expression refers to chromatin-based mechanisms that do not introduce changes in the DNA sequence per se and is not necessarily heritable
The right panel represents the semi-quantitative analysis of the protein abundance ratio to β-actin. (e) RT-qPCR was performed to assess the mRNA levels of genes (MCP-1, tumor necrosis factor (TNF), TNFR1, TGFβ1, Colα[1], αSMA, Timp[1], and Hp) associated with non-alcoholic fatty liver disease (NAFLD) as indicated (n = 6)
Inflammation, steatosis, ballooning, and fibrosis are the features of non-alcoholic fatty liver www.nature.com/scientificreports disease (NAFLD), and the associated critical bona fide genes such as monocyte chemoattractant protein-1 (MCP-1), TNF, TNFR1, TGFβ1, Colα[1], αSMA, Timp[1], and Hp were significantly enriched in the livers of mice fed an HFD
Summary
Epigenetic regulation of gene expression refers to chromatin-based mechanisms that do not introduce changes in the DNA sequence per se and is not necessarily heritable. Gene-expression regulated by epigenetic modifications, such as alter DNA accessibility and chromatin structure, histone modification, and DNA methylation[1,2]. Evidence has emerged that a link exists between glutathione (GSH) metabolism and the epigenetic regulation of redox phenomena[3,4]. CYP24A1, a gene that provides instructions for making the enzyme 24-hydroxylase, is involved in the catabolism of both 25(OH)VD3 and 1α,25(OH)2D3, thereby limiting vitamin D receptor (VDR)/1,25(OH)2D3 signaling[14]. This study examined the hypothesis that GSH-deficiency induces epigenetic alterations of VD metabolism genes, which can reduce the circulating. Western blot analysis (CYP2R1, CYP27A1, CYP27B1, CYP24A1, and VDR) performed on total protein extracts (n = 3) from the livers of mice fed an HFD for 16 weeks compared with those from mice fed the control diet.
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