However, recent analyses indicate that vitamin D affects the expression of as much as 3% of the transcribed genome in target cells including those of the immune system, skin, the pancreas and skeletal muscle (Holick, 2007). Historically, it was assumed that VDR-targeted gene expression was limited to the intestinal mucosa and bone. This newly formed complex can then bind to vitamin D response elements located upstream of vitamin D target genes, and via the recruitment of co-activators and co-repressors, leads to the activation or repression of genes, respectively (Sutton & MacDonald, 2003). Direct interaction between 1,252D3 and the VDR leads to the interaction of the 1,252D3-VDR complex with retinoid X receptor (RXR). Research over the past two decades has established that the diverse biological actions of 1,252D3 are driven through the control of gene expression, mediated by the VDR (McDonnell et al., 1987 Haussler et al., 1998) (Figure 1). For now, it is therefore recommended to always present the absolute concentration of vitamin D as well as these arbitrary definitions. However, the categorization of what constitutes 25D deficiency is widely debated (Owens et al., 2018). Vitamin D status is typically categorized using serum 25D concentrations as severely deficient ( 50 nmol/L) (The National Academies, 2011). It is this metabolite that exerts the effects of vitamin D in various tissues of the body, by binding to the VDR and subsequently regulating gene transcription.

This bioactive metabolite is transported in the blood to the target tissues expressing the vitamin D receptor (VDR). Further hydroxylation of 25D to the active form of vitamin D, termed 1,25 dihydroxyvitamin D (1,252D3, also known as calcitriol) occurs in the kidney (Figure 1). Vitamin D3 is mostly bound to the vitamin D-binding protein (DBP) in the circulation and is converted to 25-hydroxyvitamin D (25D, also known as calcifediol) in the liver under the control of the enzyme cytochrome P450 2R1 (CYP2R1) (Cheng et al., 2004 Shinkyo et al., 2004 Hamilton et al., 2010). The significance of solar vitamin D production is clear when we consider that countries with low sunlight exposure for many months of the year have populations with the lowest vitamin D concentrations (Chen et al., 2007). Produce vitamin D3, also known as cholecalciferol (Holick, 2004).

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