Role of vitamin D receptor in the regulation of gene expression

ABSTRACT

Vitamin D (VD) is a multifunctional nutrient which can be either synthesized or absorbed from the diet. It plays a pivotal role in systemic calcium and phosphate homeostasis, as well as in various physiological and pathological processes. VD is converted to the active form, 1,25-dihydroxyvitamin D (1,25-D3), by cytochrome P450 2R1 (CYP2R1)/CYP27A1 and CYP27B1 sequentially, and deactivated by multiple enzymes including CYP3A4. On the other hand, 1,25-D3 is capable of activating the transcription of genes in humans, mice and rats. The vitamin D receptor (VDR)-mediated transactivation of human and resembles that known for pregnane X receptor (PXR). Activated VDR forms a heterodimer with retinoid X receptor (RXR), recruits co-activators, translocates to the cell nucleus, binds to the specific vitamin D responsive elements (VDRE), and activates the gene transcription. In mice, intestinal mRNA levels, but not those of hepatic CYP3As, were induced by administration of VDR and PXR agonists. In rats, intestinal and mRNAs were induced by 1,25-D3 or lithocholic acid (LCA), whereas hepatic , but not and , was modulated to 1,25-D3 treatment. In general, the VDR-mediated regulation of CYP3A presents species and organ specificity.