Vitamin D Binding Protein and the Biological Activity of Vitamin D

Abstract

Vitamin D has a long-established role in bone health. In the last two decades, there has been a dramatic resurgence in research interest in vitamin D due to studies that have shown its possible benefits for non-skeletal health. Underpinning the renewed interest in vitamin D was the identification of the vital role of intracrine or localized, tissue-specific, conversion of inactive pro-hormone 25-hydroxyvitamin D [25(OH)D] to active 1,25-dihydroxyvitamin D [1,25(OH)₂D]. This intracrine mechanism is the likely driving force behind vitamin D action resulting in positive effects on human health. To fully capture the effect of this localized, tissue-specific conversion to 1,25(OH)₂D, adequate 25(OH)D would be required. As such, low serum concentrations of 25(OH)D would compromise intracrine generation of 1,25(OH)₂D within target tissues. Consistent with this is the observation that all adverse human health consequences of vitamin D deficiency are associated with a low serum 25(OH)D level and not with low 1,25(OH)₂D concentrations. Thus, clinical investigators have sought to define what concentration of serum 25(OH)D constitutes adequate vitamin D status. However, since 25(OH)D is transported in serum bound primarily to vitamin D binding protein (DBP) and secondarily to albumin, is the total 25(OH)D (bound plus free) or the unbound free 25(OH)D the crucial determinant of the non-classical actions of vitamin D? While DBP-bound-25(OH)D is important for renal handling of 25(OH)D and endocrine synthesis of 1,25(OH)₂D, how does DBP impact extra-renal synthesis of 1,25(OH)₂D and subsequent 1,25(OH)₂D actions? Are their pathophysiological contexts where total 25(OH)D and free 25(OH)D would diverge in value as a marker of vitamin D status? This review aims to introduce and discuss the concept of free 25(OH)D, the molecular biology and biochemistry of vitamin D and DBP that provides the context for free 25(OH)D, and surveys in vitro, animal, and human studies taking free 25(OH)D into consideration.

Keywords: CYP27B1; DBP; VDR; bone; free vitamin D; immunology; vitamin D.

Figure 1

Vitamin D metabolism and action. Vitamin D metabolites (Left). 7-dehydrocholesterol (7-DHC) is photoconverted to vitamin D₃ by UV exposure of skin. CYP2R1 in the liver hydroxylates vitamin D₃ to 25-hydroxyvitamin D₃ (25(OH)D). Another hydroxylation to 25(OH)D₃ by CYP27B1 occurs in the kidney but also in a number of extra-renal tissues produces the active 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). 1,25(OH)₂D₃ is the cognate ligand for the vitamin D receptor (VDR), a nuclear transcription factor, that directs 1,25(OH)₂D₃ regulated gene transcription. CYP24A1 is responsible for the hydroxylation that yields 24,25-dihydroxyvitamin D (24,25(OH)₂D₃) and subsequent catabolism to non-biologically active metabolites. Intracrine mechanism in immune cells (Right). Vitamin D action in immune cells is reliant upon the intracrine (local) production of active 1,25(OH)2D within the macrophage. Vitamin D status of the host as defined by serum, extracellular 25(OH)D levels impact immune response, as 25(OH)D is the substrate for CYP27B1. A complex interplay between monokine signaling, that can both be responsive to and stimulatory of 1,25(OH)₂D synthesis, and regulatory signaling among innate and adaptive immune cells is shown.