Vitamin D & Nuclear Receptors

Vitamin D & Nuclear Receptors

Nutritional rickets, a condition of bone growth brought on by insufficient calcium absorption from food, was the first condition for which vitamin D was found to be a cure. Vitamin D3 and vitamin D2 are referred to collectively as vitamin D. The main circulating vitamin D metabolite, 25-hydroxvitamin D (25D), has a long half-life and is produced by the 25-hydroxylation of largely hepatic vitamin D by CYP2R1, CYP27A1, and possibly other enzymes. Hormonal 1,25-dihydroxyvitamin D (1,25D) is created when CYP27B1 modifies 25D by 1-hydroxylation. Vitamin D3, the precursor of the potent steroid hormone calcitriol (1a, 25-dihydroxyvitamin D3), is essential for maintenance of heath. Using energy provided by UV-B radiation (290e315 nm), vitamin D3 can be endogenously synthesized from cutaneous 7- dehydrocholesterol in humans and most other mammals. Calcitriol has classical roles in calcium and phosphate metabolism, which is of importance in bone mineralization. In addition, accumulating data have suggested that 1a,25(OH)2D3 exerts socalled non-classical effects on cardiovascular, endocrine and immune system. The physiological functions of vitamin D are mediated by the target genes of vitamin D receptor (VDR), the only protein that binds 1a,25(OH)2D3 at sub-nanomolar concentrations. Vitamin D deficiency increases the risk of developing multiple malignancies and inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis). Although many researchers and physicians embrace this idea, it is understandable that other investigators will not accept these beneficial actions without convincing data from human randomized clinical trials (RCTs).

VDR is a nuclear receptor (NR) functioning as a transcription factor which is regulated by 1,25(OH)2D3. It is the first NR gene that was identified for human mutations. It has been found that VDR is expressed in all major target tissues of vitamin D, such as intestine, kidney, bone, and parathyroid gland, where vitamin D3 regulates calcium and phosphorus homeostasis. VDR mediates the biological actions of calcitriol primarily through genomic mechanisms. The binding of calcitriol to VDR causes the dimerization of VDR with the retinoid X receptor (RXR). The ligand-bound VDR-RXR complex further binds to vitamin D response elements (VDRE) in multiple regulatory regions located at promotors and distal sites of target genes. Through recruiting chromatin-active coregulatory complexes, VDR modulates transcription of target genes.

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