Vitamin D and DBP: the free hormone hypothesis revisited

Abstract

The last five years have witnessed a remarkable renaissance in vitamin D research and a complete re-evaluation of its benefits to human health. Two key factors have catalyzed these changes. First, it now seems likely that localized, tissue-specific, conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D) drives many of the newly recognized effects of vitamin D on human health. The second key factor concerns the ongoing discussion as to what constitutes adequate or optimal serum vitamin D (25OHD) status, with the possibility that vitamin D-deficiency is common to communities across the globe. These two concepts appear to be directly linked when low serum concentrations of 25OHD compromise intracrine generation of 1,25(OH)2D within target tissues. But, is this an over-simplification? Pro-hormone 25OHD is a lipophilic molecule that is transported in the circulation bound primarily to vitamin D binding protein (DBP). While the association between 25OHD and DBP is pivotal for renal handling of 25OHD and endocrine synthesis of 1,25(OH)2D, what is the role of DBP for extra-renal synthesis of 1,25(OH)2D? We hypothesize that binding to DBP impairs delivery of 25OHD to the vitamin D-activating enzyme 1α-hydroxylase in some target cells. Specifically, it is unbound, 'free' 25OHD that drives many of the non-classical actions of vitamin D. Levels of 'free' 25OHD are dependent on the concentration of DBP and alternative serum binding proteins such as albumin, but will also be influenced by variations in DBP binding affinity for specific vitamin D metabolites. The aim of this review will be to discuss the merits of 'free 25OHD' as an alternative marker of vitamin D status, particularly in the context of non-classical responses to vitamin D. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Keywords: Bioavailable; Free hormone; Intracrine; Megalin; Vitamin D; Vitamin D binding protein.

Figure 1. Megalin and the receptor-mediated uptake of 25-hydroxyvitamin D in the kidney

DBP-bound 25OHD in the glomerular filtrate is recovered via expression of the multi-ligand membrane receptor megalin which endocytically internalizes DBP in proximal tubule epithelial cells. The resulting release of 25OHD provides substrate for the mitochondrial 1α-hydroxylase and leads to renal synthesis of 1,25(OH)₂D to facilitate circulating levels of this hormone and support endocrine actions of this hormone, whilst also maintaining circulating levels of 25OHD.

Figure 2. A role for DBP in tissue discrimination of 25OHD2 and 25OHD3

25-hydroxyvitamin D2 (25OHD2) binds to DBP with lower affinity than 25OHD3. This will impair renal handling of 25OHD2 relative to 25OHD3, providing a potential explanation for the relative inefficiency of supplementary vitamin D2 to achieve optimal serum levels of total 25OHD relative to supplementary vitamin D3. By contrast, for extra-renal tissues such as immune cells, impaired binding of 25OHD2 to DBP may facilitate enhanced bioavailability to target cells relative to 25OHD3. In this way, a lower total serum concentration of 25OHD2 may be as effective as a higher total serum concentration of 25OHD3 in promoting intracrine synthesis of 1,25(OH)₂D and associated innate immune responses.