Pleiotropic Activities of Vitamin D Receptors - Adequate Activation for Multiple Health Outcomes

Abstract

The vitamin D receptor (VDR), a nuclear transcription factor, elicits physiological regulation of gene transcription following binding of its ligand, 1,25-dihydroxyvitamin D. The major biological activities of vitamin D contribute to regulation of plasma calcium and phosphate homeostasis and bone remodeling, although recent evidence suggests that vitamin D, like other steroid hormone receptors, can regulate a diverse range of biological activities across many tissues. Such properties raise the notion that vitamin D deficiency may not only be detrimental to bone and muscular health, but also a risk factor for a number of adverse health outcomes including increased risk of cardiovascular disease, inflammation, immune system disorders and cancer. Advances in transcriptional research provide data not only on ligand-dependent activities of the VDR, but other activities of vitamin D extending to rapid modulation of intra-cellular signaling pathways as well as apparent ligand-independent interactions between the VDR and other transcriptionally active proteins. In this review, we detail the chief molecular activities of the VDR in regulating gene transcription, intracellular signaling and actions of VDR via binding to transcriptional regulating proteins. The breadth of biological activities attributed to vitamin D informs clinical biochemists and health care professionals on the implications of vitamin D deficiency for health.

Figure 1.

Classical pathway of VDR mediated gene regulation. Exogenous 1,25D enters the cell and binds to the classical VDR, initiating heterodimerisation with RXR. The VDR-RXR complex then binds to a vitamin D responsive element within the genome and directs the formation of a large transcriptional complex. (a) For activation of vitamin D responsive genes, the transcriptional complex recruits co-activators such as NCoA62, steroid receptor co-activator-1 (SRC-1), CREB-binding protein (CBP) and P300 to initiate histone acetylation. Next, VDR-RXR synergises with mediator of RNA polymerase II transcription subunit 1 (MED1) to recruit molecular machinery such as RNA polymerase II for upregulation of gene transcription. (b) VDRRXR complex can act in unison with co-repressors such as nuclear receptor co-repressor (NCOR) and histone deactylases (HDACs) to repress gene transcription