Vitamin D and Health

2.49 A number of studies have reported adiposity and body mass index (BMI) to be inversely related to
serum 25(OH)D concentrations (Liel et al., 1988; Arunabh et al., 2003; Parikh et al., 2004; Snijder et al.,
2005) suggesting vitamin D is not readily available from adipose tissue and that, because of its
lipophilic nature, it is sequestered rather than stored. This is supported by some studies which
reported increases in serum 25(OH)D concentrations with weight reduction in obese individuals
(Zittermann et al., 2009; Tzotzas et al., 2010).
2.50 Details about accumulation and mobilisation of vitamin D stores from adipose tissue and other tissues
such as muscle are not clear at this time (IOM, 2011).
Mechanism of action
2.51 1,25(OH) 2 D elicits a biological response through the regulation of gene transcription (genomic
response) and by activating signal transduction pathways at or near plasma membranes (non-genomic
or rapid response) (Norman et al., 2004). The mechanism of action is mediated through binding with a
single vitamin D receptor (VDR) (DeLuca, 2004). After formation in the kidney, 1,25(OH) 2 D enters the
circulation bound to DBP.
2.52 The VDR has a high affinity for 1,25(OH) 2 D 3 (Norman, 2008). 1,25(OH) 2 D 2 and 1,25(OH) 2 D 3 appear to
be similar in their binding affinity to VDR (DeLuca, 2008). The VDR is expressed in cells involved in
calcium and phosphate homeostasis, e.g., enterocytes, osteoblasts, parathyroid and distal renal tubule
cells (Jones et al., 1998). VDRs are also present in a wide range of other cells and tissues including
macrophages, lymphocytes, skin keratinocytes, pancreatic ß-islet cells, ovarian tissue, mammary
epithelium, neuronal tissue, lung, gonads, prostate, placenta, and adipose tissue (Jones et al., 1998;
Norman, 2008). Its function in these tissues is not fully understood.
2.53 The amount of VDR expressed in different tissues varies widely and appears to be regulated in some
tissues (e.g., kidney, parathyroid) but not in others (Dame et al., 1986; Brown & Slatopolsky, 2007).
Many VDR expressing cells also possess the enzyme CYP27B1 and therefore have the capacity to
produce 1,25(OH) 2 D (Bikle, 2009).
Genomic response
2.54 The VDR functions in the nucleus of cells as a heterodimer with a retinoid X receptor (RXR) to regulate
vitamin D target genes. The heterodimeric complex interacts with vitamin D-responsive elements
(VDREs), which are repeat sequences of 6 nucleotides separated by 3 non-specified bases within the
promoter region of target genes, resulting in activation or repression of transcription (Rachez &
Freedman, 2000; Christakos et al., 2003; DeLuca, 2004).
Non-genomic response
2.55 Non-genomic responses of 1,25(OH) 2 D are mediated by the interaction of the VDR with caveolae
(membrane invaginations) which are present in the plasma membrane of a variety of cells
(Huhtakangas et al., 2004). Upon activation by 1,25(OH) 2 D, VDRs may elicit a cellular response on
calcium channels through second messengers such as mitogen-activated protein kinase or cyclic
adenosine monophosphate (Feldman et al., 2005). Rapid response mechanisms, through membrane
VDRs and second messengers operate in the intestine, vascular smooth muscle, pancreatic β-cells and
monocytes (Lips, 2006).
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