ReviewVitamin D cell signalling in health and disease
Introduction
Vitamin D deficiency is a major world pandemic [1], [2]. The first clear indication that such a deficiency can cause disease emerged when rickets was found to result from a decline in calcium (Ca2+) uptake across the intestine caused by low levels in Vitamin D. Subsequently, such Vitamin D deficiencies have been linked to many other human diseases such as Alzheimer's disease (AD), cancer, cardiovascular disease, hypertension, type II diabetes, multiple sclerosis (MS), Parkinson's disease (PD) and various inflammatory disorders such as tuberculosis [3]. The role of vitamin D in preventing rickets depends on its ability to increasing the expression of Ca2+ pumps and buffers to facilitate the uptake of Ca2+ across the intestine as part of vitamin D's role in regulating whole body Ca2+ homoeostasis. In the case of all the other diseases mentioned above, there is no general consensus as to how Vitamin D might function despite the overwhelming evidence of its important health benefits.
In this review, I will develop the concept that Vitamin D may act by maintaining the stability of intracellular signalling pathways. This Vitamin D phenotypic stability hypothesis will be illustrated through its role in regulating the cellular mechanisms responsible for maintaining the Ca2+ and redox signalling pathways.
Section snippets
Vitamin D biosynthesis, metabolism and mode of action
The active component of vitamin D is 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] that is formed by a series of reactions that take place in a number of different tissues (Fig. 1). The first reaction is driven by sunlight acting on the skin [4] to photolyze 7-dehydrocholesterol to vitamin D3 (cholecalciferol), which is transferred to the liver where a hydroxyl group is added to the C-25 position by a vitamin D-25 hydroxylase (encoded by the CYP27A1 gene) to form 25-hydroxyvitamin D3 [25(OH)D3] that
Vitamin D a guardian of signalling phenotypic stability
When cells differentiate, they usually stop proliferating and begin to express cell-type-specific signalling mechanisms appropriate to control their designated function. It is essential that such signalling systems are maintained so that they can continue to deliver the signals appropriate for their particular function. There is increasing evidence that vitamin D regulates the expression of many components of different signalling pathways, such as those activated by insulin, ETS, tumour
Vitamin D deficiency in ageing and human disease
A deficiency in Vitamin D has been linked to many human diseases [3], [22], [101], [102], [103]. There are multiple polymorphisms of the VDR gene and some of these have been associated with various disorders including autoimmune diseases and cancer. A characteristic of many of these diseases is that they are age-related in that they begin to emerge later in life. The ageing process, which is still not properly understood, seems to be driven by a number of processes that result in a gradual
Vitamin D and neurodegenerative diseases
There are an increasing number of studies indicating that a deficiency in vitamin D may contribute to the onset of neurodegenerative diseases such as Alzheimer's disease (AD), autism, depression, Parkinson's disease (PD), schizophrenia and multiple sclerosis (MS) [158], [159]. Neurons strongly express the vitamin D receptor (VDR) and VDR polymorphisms have been associated with PD [160], AD [161], [162], [163], [164] and have been linked to an age-related decline in cognition. Increased Ca2+ and
Vitamin D and cardiovascular disease
Hypertension and cardiovascular diseases have been linked to vitamin D deficiency [102], [103], [260], [261], [262], [263], [264]. Protection of the cardiovascular system by vitamin D occurs at multiple levels and is highlighted by its role in guarding the stability of the ROS and Ca2+ signalling systems that are dysregulated in hypertension, cardiac hypertrophy, congestive heart failure (CHF) and atrial arrhythmias.
Vitamin D in adaptive immunity and autoimmune diseases
Vitamin D can modulate both adaptive and innate immunity. A deficiency in Vitamin D has been linked to a number of autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, multiple sclerosis (MS) and inflammatory bowel disease [303]. In animal models, many of these diseases can be prevented by administering Vitamin D [304], [305]. Autoimmunity arises when T helper-1 (Th1) cells are misdirected against self-proteins [303]. Vitamin D acts to represses the proliferation of these Th1
Vitamin D in innate immunity and infectious disease
Vitamin D has an important role in the innate immune response and its deficiency is linked to a number of infectious diseases such as tuberculosis, septicaemia, influenza, pneumonia and periodontal disease [3], [334], [335]. Adequate levels of vitamin D are required to initiate antimicrobial responses [336], [337]. Indeed, one of the initial responses is to increase the expression of both 25(OH)2D3-1α-hydroxylase (encoded by the CYP27B1 gene) and the VDR [337]. The former enhances the local
Conclusion
The Vitamin D phenotyopic stability hypothesis attempts to explain why its deficiency contributes to the development of so many chronic disease states. Many of these diseases are often associated with alterations in both Ca2+ and redox signalling, both of which are regulated by Vitamin D operating together with Klotho and Nrf2. The basis of this stability hypothesis, therefore, is that any reduction in Vitamin D levels will contribute to the development of these disease states as a result of
Conflict of interest
None declared.
References (343)
The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action
Mol. Asp. Med.
(2008)- et al.
Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)vitamin D: genomic and non-genomic mechanisms
Best Pract. Res. Clin. Endocrinol. Metab.
(2011) - et al.
The Vitamin D receptor: new paradigms for the regulation of gene expression by 1,25-Dihydroxyvitamin D3
Endocrinol. Metab. Clin. North Am.
(2010) - et al.
Hydralazine-induced promoter demethylation enhances sarcoplasmic reticulum Ca2+ -ATPase and calcium homeostasis in cardiac myocytes
Lab. Invest
(2011) - et al.
Epigenetic GABAergic targets in schizophrenia and bipolar disorder
Neuropharmacology
(2011) - et al.
VDR primary targets by genome-wide transcriptional profiling
J. Steroid Biochem. Mol. Biol.
(2014) - et al.
A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response
Cell
(2013) - et al.
Suppression of death receptor-mediated apoptosis by 1,25-dihydroxyvitamin D3 revealed by microarray analysis
J. Biol. Chem.
(2005) Vitamin D and the dual processes of intestinal calcium absorption
J. Nutr.
(2004)- et al.
The Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Trends Biochem. Sci.
(2014)
Nrf2:INrf2 (Keap1) signaling in oxidative stress
Free Radic. Biol. Med.
Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases
Biochem. Pharmacol.
Carnosic acid induces the NAD(P)H: quinone oxidoreductase 1 expression in rat clone 9 cells through the p38/Nuclear factor erythroid-2 related factor 2 pathway
J. Nutr.
Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression
Free Radic. Biol. Med.
Carcinogenesis and its role in cadmium-induced Nrf2/p62 signaling in apoptosis resistance
J. Biol. Chem.
Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis
J. Biol. Chem.
Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β
Neurobiol. Dis.
Functional interference between glycogen synthase kinase-3 beta and the transcription factor Nrf2 in protection against kainite-induced hippocampal cell death
Mol. Cell. Neurosci.
Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2
J. Biol. Chem.
Vitamin D receptor controls expression of the anti-aging Klotho gene in mouse and human renal cells
Biochem. Biophys. Res. Commun.
Morphological and biochemical signs of age-related neurodegenerative changes in Klotho mutant mice
Neuroscience
Current understanding of Klotho
Ageing Res. Rev.
Regulation of multiple ageing-like phenotypes by inducible Klotho gene expression in Klotho mutant mice
Mech. Ageing Dev.
KLOTHO allele status and the risk of early-onset occult coronary artery disease
Am. J. Hum. Genet.
Regulation of oxidative stress by the anti-aging hormone klotho
J. Biol. Chem.
Regulation of angiogenesis by the aging suppressor gene Klotho
Biochem. Biophys. Res. Commun.
Klotho protein protects against endothelial dysfunction
Biochem. Biophys. Res. Commun.
The neuroprotective Effect of Klotho is mediated via regulation of members of the redox system
J. Biol. Chem.
Life extension factor klotho enhances cognition
Cell. Rep.
The redox proteme
J. Biol. Chem.
Role of metabolic H2O2 generation: redox signalling and oxidative stress
J. Biol. Chem.
Cellular signalling of the receptor for advanced glycation end products (RAGE)
Cell. Signal
Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts
Int. J. Cardiol.
Oxidant sensing by reversible disulphide bond formation
J. Biol. Chem.
Decrease in age-related tau hyperphosphorylation and cognitive improvement following vitamin D supplementation are associated with modulation of brain energy metabolism and redox state
Neuroscience
Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes
Biochem. Biophys. Res. Commun.
The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor
J. Biol. Chem.
Sulfhydryl reagents and cAMP-dependent kinase increase the sensitivity of the inositol 1,4,5-trisphosphate receptor in hepatocytes
J. Biol. Chem.
Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species
J. Biol. Chem.
X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca2+](i)
J. Mol. Cel.l Cardiol.
Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline
J. Clin. Endocrinol. Metab.
The health benefits of solar irradiance and Vitamin D and the consequences of their deprivation
Clinic. Rev. Bone Miner. Metab.
Photosynthesis of previtamin D3 in human skin and the physiologic consequences
Science
Update on the biologic role of vitamin D on the endocrine system
Curr. Vasc. Pharmacol.
Vitamin D
Am. J. Physiol. Renal Physiol.
Interaction of vitamin with membrane-based signaling pathways
Front. Physiol.
Vitamin D and the epigenome
Front. Physiol.
Promoter methylation and age-related downregulation of Klotho in rhesus monkey
Age
Theranti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma
Mol. Cancer
Do age-related changes in DNA methylation play a role in the development of age-related diseases?
Biochem. Soc. Trans.
Cited by (148)
Magnetic resonance spectroscopy in the hippocampus of adult APP/PS1 mice following chronic vitamin D deficiency
2024, Behavioural Brain ResearchCalcitriol modulates epidermal tight junction barrier function in human keratinocytes
2024, Journal of Dermatological ScienceVitamin D and cancer
2024, Advances in Food and Nutrition ResearchOxidative stress: A common pathological state in a high-risk population for osteoporosis
2023, Biomedicine and Pharmacotherapy