Epigenetic modifications of vitamin D-regulatory genes and glutathione-deficiency in FL83B mouse hepatocytes and the liver of HFD-induced diabetic mice

Vitamin D (VD) deficiency is an epidemic health problem. VD-regulates the functions of over 200 genes and is essential for growth and development. VD-deficiency can result in diabetes, hypertension, heart disease and stroke. VD levels correlate positively with GSH and negatively with insulin resistance in type 2 diabetic patients. High-fat-diet (HFD) fed mice (16 weeks) exhibited elevated blood glucose and decreased blood GSH and 25(OH)VD3 with reduced GSH and increased oxidative stress in the liver compared with control (normal diet) group. We investigated the hypothesis that GSH-deficiency induces epigenetic alterations in the VD-metabolism genes leading to 25(OH)VD3-deficiency in HFD-fed mice. The levels of VD-metabolism genes [25-hydroxylase (CYP2R1, CYP27A1), 1-alpha-hydroxylase (CYP27B1), VDR] and GSH biosynthesis pathway genes were significantly down-regulated in the liver of HFD-fed mice. Conversely, 24-hydroxylase (CYP24A1) which metabolizes the active-VD was significantly increased. Notably, significant gene-specific hypermethylation of CYP2R1 (1.71, 2.55; Control vs. HFD), CYP27A1 (7.58, 8.68), CYP27B1 (0.11, 0.77), VDR (0.16, 0.46) and hypomethylation of CYP24A1 (0.59, 0.33) was observed in the liver of HFD-fed mice compared with the control group (p