Vitamin D homeostasis is maintained by the synthetic activity of 1a-hydroxylase and catabolic activity of 24-hydroxylase (CYP24A1). 1,25(OH)2D3 regulates 1a-hydroxylase activity both directly through negative feedback but also by way of inhibition of parathyroid hormone (PTH) activity. Conversely, in response to hypocalcemia, PTH increases 1a-hydroxylase transcription and, therefore, 1,25(OH)2D3 synthesis through a cyclic adenosine monophosphate (cAMP)-dependent pathway. Another mediator of vitamin D homeostasis is fibroblast growth factor 23 (FGF23) which is produced primarily by osteoblasts and
osteocytes and influences vitamin D metabolism through down-regulation of 1a-hydroxylase activity and promotion of 24-hydroxylase activity. Sex hormones, calcitonin, and prolactin
can also affect vitamin D homeostasis, though 1a-hydroxylase activity remains INCB024360 the primary factor Romidepsin manufacturer in vitamin D homeostasis. In addition to sun exposure and diet, vitamin D levels may also be affected by genetic factors and high heritability of VDD has been shown in several epidemiologic studies.[5, 6] The exact genes involved have only recently been investigated, with the most substantial study to date showing single nucleotide polymorphisms (SNPs) in the genes encoding CYPR21 and DBP were associated with vitamin D status in an initial cohort of 156 unrelated healthy Caucasians and a similar replication cohort of 340 patients. Given the essential role of CYPR21 and DBP in vitamin D homeostasis, these findings are not surprising and have been replicated in other studies. Interestingly, the study by Ramos-Lopez et al. associated the CYP2R1 gene with both vitamin D levels and type 1 diabetes, although no data exist evaluating the SNPs associated with vitamin D levels in NAFLD patients. Conversely, the genes associated with a high incidence of NAFLD have not been evaluated Bay 11-7085 for a putative role in vitamin D metabolism. The primary mediator of vitamin D is the vitamin D nuclear
receptor (VDR), which is a member of the superfamily of nuclear hormone receptors. VDR has four major domains that interact to confer ligand-activated transcription factor activity: a ligand-binding domain, a retinoid X receptor (RXR) heterodimerization domain, a DNA binding domain to vitamin D response elements, and a recruitment domain of VDR coregulators. VDR bound to RXR forms a heterodimer that interacts with vitamin D response elements (VDRE) located within promoter regions of target genes and leads to activation or repression of transcription. Target genes of the VDR are broad and include functions of hormone secretion, immune regulation, cellular proliferation, and differentiation. The nonclassic actions of vitamin D can be grouped into three primary categories to include modulation of immunologic function, hormone secretion, and cellular proliferation and differentiation (Fig. 1).