Vitamin D in dairy cows: metabolism, status and functions in the immune system

Figures & data

Figure 1. Metabolism of vitamin D. Vitamin D synthetised in the skin or deriving from the feed is absorbed in the small intestine and delivered to the liver where it is hydroxylated to 25-hydroxyvitamin D [25(OH)D] by various 25-hydroxylases (CYP2R1, CYP27A1, CYP3A4, CYP2J2). 25(OH)D is transported to the kidney, where it is hydroxylated by CYP27B1 to 1,25-dihydroxyvitamin D [1,25(OH)₂D], the biological active metabolite of vitamin D. Both, 25(OH)D and 1,25(OH)₂D are also hydroxylated, mainly by CYP24A1, to non-bioactive metabolites which are excreted via urine or bile. The activities of CYP27B1 and CYP24A1 are regulated by various factors [concentrations of phosphorus (P), calcium (Ca), fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), 1,25(OH)₂D] in order to maintain the concentration of 1,25(OH)₂D at a physiological level. In the blood, the vitamin D metabolites are primarily bound to vitamin D binding protein (DBP), but a small percentage is also available in free form. Cells expressing the megalin/cubulin receptor are able to take up DBP-bound vitamin D metabolites [25(OH)D, 1,25(OH)₂D] by endocytosis. In cells not expressing the megalin/cubulin receptor vitamin D metabolites in free (unbound) form are taken up by diffusion. Cells expressing CYP27B1 are able to form 1,25(OH)₂D from 25(OH)D. Within the cell 1,25(OH)₂D binds to the vitamin D receptor (VDR), which dimerises with retinoid X receptor (RXR) and other cofactors. The VDR-RXR complex binds to vitamin D response element (VDRE) of the DNA and mediates the effects of vitamin D by regulating the transcription of target genes. For more detail and references, see text.

Table 1. Cell types capable of autocrine vitamin D signalling by co-expressing CYP27B1 and VDR (Chun et al. 2019)

Macrophage	Enterocyte
Dendritic cell	Decidual stromal cell
Parathyroid cell	Foetal trophoblast
Osteoblast	Prostate epithelial cell
Osteoclast	Vascular endothelial cell
Keratinocyte	Pancreatic ß-cell
Mammary epithelial cell	Renal tubular cell

Figure 2. Model of the effects of vitamin D on bovine immune cells (macrophages, monocytes) and mammary epithelial cells. Pathogen-associated molecular patterns (PAMP) like lipopolysaccharides (LPS) bind to their receptors like toll-like receptors (TLR), and thereby initiate an immune response in the cell. The initiation of the immune response leads to an upregulation of CYP27B1 and vitamin D receptor (VDR). Activation of CPY27B1 causes an increased production of 1,25-dihydroxyvitamin D [1,25(OH)₂D] from its precursor 25-hydroxyvitamin D [25(OH)D] which is taken up from the blood. 1,25(OH)₂D then binds to the VDR, which after complexing with retinoid X receptor (RXR) and other cofactors, binds to vitamin D response element (VDRE) and induces the transcription of “regulated and normal T cells expressed and secreted” (RANTES), “inducible nitric oxide synthase” (iNOS) and ß-defensins, representing genes known to improve the innate immune response. For more details and references, see text.

Chun RF, Shieh A, Gottlieb C, Yacoubian V, Wang J, Hewison M, Adams JS. 2019. Vitamin D binding protein and the biological activity of vitamin D. Front Endocrinol (Lausanne). 10:718.

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