Vitamin D


The fat‐soluble secosteroid vitamin D3 is synthesised in UV (ultraviolet)‐B exposed human skin. It regulates calcium and phosphorus homeostasis and thus plays an important role in bone mineralisation. Moreover, vitamin D3 contributes to the control of cellular growth and differentiation as well as to the responsiveness of the innate and adaptive immune system. At insufficient sun exposure, the molecule is a true vitamin and needs to be taken up via diet or by direct supplementation with pills. During the past 50 000 years, the need of sufficient vitamin D3 synthesis acted an evolutionary driver for skin lightening of anatomically modern humans migrating out of Africa. The vitamin D3 metabolite 1α,25‐dihydroxyvitamin D3 is the exclusive high‐affinity ligand of the transcription factor vitamin D receptor and has a direct effect on the expression of >1000 genes. Thus, vitamin D3 is a modulator of the human epigenome and transcriptome in more than half of all human tissues and cell types.

Key Concepts

  • In UV‐B exposed human skin, the cholesterol precursor 7‐dehydrocholesterol converts to pre‐vitamin D3 and then isomerises in a nonenzymatic reaction into vitamin D3.
  • Lifestyle changes significantly reduced the average endogenous vitamin D3 production in human and caused vitamin D deficiency in most human populations.
  • Vitamin D3 is a biologically inert molecule and is enzymatically converted in a two‐step reaction to the nuclear hormone 1,25(OH)2D3.
  • 25(OH)D3 serum levels are used as biomarker for the vitamin D status.
  • Only vertebrates have a full vitamin D endocrine system, formed by plasma transport proteins, metabolising enzymes and a high‐affinity receptor.
  • The migration of modern humans to less sunny regions in Asia and Europe caused an evolutionary pressure for genetic adaptation in form of gradual skin lightening for more efficient vitamin D3 production.
  • The genome‐wide VDR binding pattern is rather cell‐specific, which has an impact on the panel of vitamin D target genes in VDR expressing tissues and cell types.
  • Vitamin D3 has a direct effect on the accessibility of chromatin, that is it serves as a modulator of the epigenome.
  • Humans have an individual response to vitamin D3, referred to a vitamin D response index, which allows segregation into high, mid and low responders.
  • The vitamin D response index suggests for each individual a vitamin D3 supplementation protocol that will direct to a personal optimal vitamin D status.

Keywords: vitamin D; VDR; epigenome; transcriptome; gene regulation; UV‐B exposure; immune system; evolution

Figure 1. Vitamin D synthesis pathway. Vitamin D3 is synthesised endogenously in the skin under essential catalysis by UV‐B or taken up by diet. In the liver, vitamin D3 is converted by the enzyme CYP2R1 into the circulating form 25(OH)D3 and then in the kidneys (and in many additional tissues and cell types) by the enzyme CYP27B1 into the high‐affinity VDR ligand 1,25(OH)2D3.
Figure 2. Structural view. The structure of 1,25(OH)2D3 (a) and of VDR's LBD (b). The LBP is indicated in red. Please note that both structures are in different scale.


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Further Reading

Campbell MJ (2017) Bioinformatic approaches to interrogating vitamin D receptor signaling. Mol Cell Endocrinol 453: 3–13.

Fleet JC (2017) The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol Cell Endocrinol 453: 36–45.

Hollis BW and Wagner CL (2017) Vitamin D supplementation during pregnancy: improvements in birth outcomes and complications through direct genomic alteration. Mol Cell Endocrinol 453: 113–130. (accessed 14 Dec 2017).

Lorenzen M, Boisen IM, Mortensen LJ, et al. (2017) Reproductive endocrinology of vitamin D. Mol Cell Endocrinol 453: 103–112.

Maestro MA, Molnar F, Mourino A and Carlberg C (2016) Vitamin D receptor 2016: novel ligands and structural insights. Expert Opin Ther Pat 26: 1291–1306.

Rochel N and Molnar F (2017) Structural aspects of Vitamin D endocrinology. Mol Cell Endocrinol 453: 22–35.

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Carlberg, Carsten(Feb 2018) Vitamin D. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027820]