Trends in Endocrinology & Metabolism
ReviewVitamin D: newly discovered actions require reconsideration of physiologic requirements
Section snippets
Vitamin D production
Two forms of vitamin D exist: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) (Figure 1). The former is produced in the skin under the influence of ultraviolet B radiation (UVR), whereas the latter, also produced by UVR, is produced in a variety of plant materials and yeast. Differences exist in their binding to the major transport protein in blood, vitamin D binding protein (DBP) and in their metabolism because of the different structures of their side chains. In humans, 25OHD2 is
Vitamin D metabolism
To be biologically active, vitamin D must first be converted to 25OHD (Figure 1). Several enzymes, both mitochondrial and microsomal, are capable of this function [7]. These enzymes are found in many tissues and their activity is limited primarily by substrate (i.e. vitamin D) availability [8]. As such, serum 25OHD is a reliable indicator of vitamin D status [9]. To be fully active, 25OHD must be further converted to 1,25(OH)2D via CYP27B1. Although the proximal renal tubule is the major source
Regulation of hormone secretion
1,25(OH)2D regulates the production and secretion of several hormones (Figure 3), which in some cases feedback on renal production of 1,25(OH)2D3. Vitamin D deficiency has been linked to a variety of diseases resulting from either over or under secretion of such hormones, providing a physiologic basis for the importance of this regulation. The following are examples.
Regulation of immune function
The potential role for vitamin D and its active metabolite 1,25(OH)2D to modulate the immune response rests on the observations that VDRs are found in activated dendritic cells, macrophages and lymphocytes 46, 47, that these cells produce 1,25(OH)2D (i.e. express CYP27B1) [46], and that 1,25(OH)2D regulates their proliferation and function [48]. Two forms of immunity exist – adaptive and innate – and each are regulated by 1,25(OH)2D (Figure 4).
Regulation of proliferation and differentiation
The proliferation and differentiation of many cell types is controlled, at least to some degree, by vitamin D and its metabolites. As such, the role of vitamin D in the prevention and/or treatment of conditions where such regulation goes awry has been the focus of considerable attention. Much interest has focused on cancer prevention and treatment. 1,25(OH)2D has been evaluated for its potential anticancer activity in animal and cell studies. The list of malignant cells that express VDR is now
Defining vitamin D sufficiency
Serum 25OHD levels, collectively constituted by 25OHD2 from nutritional sources and 25OHD3 from both cutaneous sources and nutritional sources, provide a useful surrogate for assessing vitamin D status. 1,25(OH)2D levels, unlike 25OHD levels, are well maintained until the extremes of vitamin D deficiency because of secondary hyperparathyroidism, and thus do not provide a useful index for assessing vitamin D deficiency at least at the initial stages. Historically, vitamin D sufficiency was
Summary and concluding remarks
Vitamin D regulates numerous physiologic processes in addition to maintaining calcium homeostasis through its actions on bone, intestine and kidney. These non-classical actions include regulating the production and secretion of several hormones, controlling cellular proliferation and differentiation, and modulating both the adaptive and innate immune response. These pleiotropic actions reflect the ubiquitous distribution of VDR and the enzyme, CYP27B1, that produces the preferred ligand for
Glossary
- CYP27B1
- 25OHD 1α hydroxylase [the enzyme that produces 1,25(OH)2D].
- CYP24
- 25OHD 24 hydroxylase [the enzyme that degrades 1,25(OH)2D and 25OHD].
- 1,25(OH)2D
- 1,25 dihydroxyvitamin D, the preferred ligand for the vitamin D receptor.
- 7-DHC
- 7 dehydrocholesterol, the precursor in skin for vitamin D production.
- DBP
- vitamin D binding protein, the major carrier of vitamin D metabolites in the circulation.
- DM
- diabetes mellitus.
- FGF23
- fibroblast growth factor 23, a major regulator of phosphate reabsorption and 1,25(OH)2
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