Health Risks of Hypovitaminosis D: A Review of New Molecular Insights

Abstract

Hypovitaminosis D has become a pandemic, being observed in all ethnicities and age groups worldwide. Environmental factors, such as increased air pollution and reduced ultraviolet B (UVB) irradiation, as well as lifestyle factors, i.e., decreased outdoor activities and/or poor intake of vitamin D-rich food, are likely involved in the etiology of a dramatic reduction of vitamin D circulating levels. The insufficiency/deficiency of vitamin D has long been known for its association with osteoporosis and rickets. However, in the last few decades it has become a serious public health concern since it has been shown to be independently associated with various chronic pathological conditions such as cancer, coronary heart disease, neurological diseases, type II diabetes, autoimmune diseases, depression, with various inflammatory disorders, and with increased risk for all-cause mortality in the general population. Prevention strategies for these disorders have recently involved supplementation with either vitamin D2 or vitamin D3 or their analogs at required daily doses and tolerable upper-limit levels. This review will focus on the emerging evidence about non-classical biological functions of vitamin D in various disorders.

Keywords: VDR; allergy; cardiovascular diseases (CVD); central nervous system (CNS); microbioma; vitamin D.

Figure 1

VDR heterodimer transcription complex and VDR distribution throughout the human body (brown small and big dots) and. Tissue targets of VDR are the following: skin, brain regions, spinal cord, pituitary gland, salivary glands, nasal-oral mucosa, teeth, parathyroid, thymus, lung, heart, spleen, pancreas, adrenal gland, kidney, esophagus, stomach, pylorus, small intestine, large intestine, testis, prostate, bone, immune cells, others. On the left and right of the figure are shown some of VDR old (cardiovascular system) and emerging tissue targets (brain, intestinal microbioma, mast cells). Some of main known VDR gene targets in these latter are shown (in green, up-regulated; in red, down-regulated): ATG16L1, Autophagy-related protein 16-1; BDNF, brain-derived neurotrophic factor; CACNA1C, L-type voltage-sensitive calcium channel subunit A1C; CAMP, cathelicidin antimicrobial peptide; CNTF, ciliary neurotrophic factor; COMT, catechol-O-methyl-transferase; COX, cycloxygenase; DRD2, dopamine receptor D2; ECE1, Endothelin 1-converting enzyme; FCER1A, Fc fragment of IgE receptor IA; GDNF, glia-derived neurotrophic factor; IFNG, Interferon-γ; IL3RA, IL-3 receptor-alpha chain; KIT, gene-encoding CD117; NGF, nerve growth factor; NOS3, endothelial nitric oxide synthase; NT3, neurotrophin 3; Nurr1, nuclear receptor related 1 protein; SERPINE1, serine-protease inhibitor 1 (PAI-1); REN, Renin; RXR, retinoid X receptor; TBP, TATA-binding protein; TFIIB, transcripton factor IIB; THBS1, Thrombospondin-1; TRPV6, transient receptor potential cation channel subfamily V member 6; VDRE, vitamin D response elements on DNA sequence; VD, vitamin D.