Review
Vitamin D cell signalling in health and disease

https://doi.org/10.1016/j.bbrc.2015.01.008Get rights and content

Highlights

  • Vitamin D deficiency causes many human diseases.

  • A phenotypic stability hypothesis explains how Vitamin D maintains cellular functions.

  • Vitamin D maintains the redox and Ca2+ signalling systems.

  • Vitamin D increases expression of Nrf2 and Klotho that also control Ca2+ and redox signalling.

  • Many major diseases are caused by a decline in the Vitamin D/klotho/Nrf2 regulatory network.

Abstract

Vitamin D deficiency has been linked to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. A Vitamin D phenotypic stability hypothesis, which is developed in this review, attempts to describe how this vital hormone acts to maintain healthy cellular functions. This role of Vitamin D as a guardian of phenotypic stability seems to depend on its ability to maintain the redox and Ca2+ signalling systems. It is argued that its primary action is to maintain the expression of those signalling components responsible for stabilizing the low resting state of these two signalling pathways. This phenotypic stability role is facilitated through the ability of vitamin D to increase the expression of both Nrf2 and the anti-ageing protein Klotho, which are also major regulators of Ca2+ and redox signalling. A decline in Vitamin D levels will lead to a decline in the stability of this regulatory signalling network and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca2+ signalling.

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)

  • J.W. Kaspar et al.

    Nrf2:INrf2 (Keap1) signaling in oxidative stress

    Free Radic. Biol. Med.

    (2009)
  • H. Saito

    Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases

    Biochem. Pharmacol.

    (2013)
  • C.-W. Tsai et al.

    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.

    (2011)
  • W. Jeong et al.

    Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression

    Free Radic. Biol. Med.

    (2012)
  • Y.-O. Son et al.

    Carcinogenesis and its role in cadmium-induced Nrf2/p62 signaling in apoptosis resistance

    J. Biol. Chem.

    (2014)
  • S.K. Niture et al.

    Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis

    J. Biol. Chem.

    (2012)
  • F. Correa et al.

    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.

    (2011)
  • A.L. Rojo et al.

    Functional interference between glycogen synthase kinase-3 beta and the transcription factor Nrf2 in protection against kainite-induced hippocampal cell death

    Mol. Cell. Neurosci.

    (2008)
  • M. Salazar et al.

    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.

    (2006)
  • R.E. Forster et al.

    Vitamin D receptor controls expression of the anti-aging Klotho gene in mouse and human renal cells

    Biochem. Biophys. Res. Commun.

    (2011)
  • M. Shiozaki et al.

    Morphological and biochemical signs of age-related neurodegenerative changes in Klotho mutant mice

    Neuroscience

    (2008)
  • Y. Wang et al.

    Current understanding of Klotho

    Ageing Res. Rev.

    (2009)
  • H. Masuda et al.

    Regulation of multiple ageing-like phenotypes by inducible Klotho gene expression in Klotho mutant mice

    Mech. Ageing Dev.

    (2005)
  • D.E. Arking et al.

    KLOTHO allele status and the risk of early-onset occult coronary artery disease

    Am. J. Hum. Genet.

    (2003)
  • M. Yamamoto et al.

    Regulation of oxidative stress by the anti-aging hormone klotho

    J. Biol. Chem.

    (2005)
  • K. Fukino et al.

    Regulation of angiogenesis by the aging suppressor gene Klotho

    Biochem. Biophys. Res. Commun.

    (2002)
  • Y. Saito et al.

    Klotho protein protects against endothelial dysfunction

    Biochem. Biophys. Res. Commun.

    (1998)
  • E. Zeldich et al.

    The neuroprotective Effect of Klotho is mediated via regulation of members of the redox system

    J. Biol. Chem.

    (2014)
  • D.B. Dubal et al.

    Life extension factor klotho enhances cognition

    Cell. Rep.

    (2014)
  • Y.-M. Go et al.

    The redox proteme

    J. Biol. Chem.

    (2013)
  • H. Sies

    Role of metabolic H2O2 generation: redox signalling and oxidative stress

    J. Biol. Chem.

    (2014)
  • J. Xie et al.

    Cellular signalling of the receptor for advanced glycation end products (RAGE)

    Cell. Signal

    (2013)
  • T.W. Lee et al.

    Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts

    Int. J. Cardiol.

    (2014)
  • C.M. Cremers et al.

    Oxidant sensing by reversible disulphide bond formation

    J. Biol. Chem.

    (2013)
  • T.L. Briones et al.

    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

    (2014)
  • S.K. Jain et al.

    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.

    (2013)
  • M.D. Bootman et al.

    The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor

    J. Biol. Chem.

    (1992)
  • G.S. Bird et al.

    Sulfhydryl reagents and cAMP-dependent kinase increase the sensitivity of the inositol 1,4,5-trisphosphate receptor in hepatocytes

    J. Biol. Chem.

    (1993)
  • S. Bánsághi et al.

    Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species

    J. Biol. Chem.

    (2014)
  • B.L. Prosser et al.

    X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca2+](i)

    J. Mol. Cel.l Cardiol.

    (2013)
  • M.F. Holick et al.

    Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline

    J. Clin. Endocrinol. Metab.

    (2011)
  • W.R. Grant

    The health benefits of solar irradiance and Vitamin D and the consequences of their deprivation

    Clinic. Rev. Bone Miner. Metab.

    (2009)
  • H.F. Holick et al.

    Photosynthesis of previtamin D3 in human skin and the physiologic consequences

    Science

    (1980)
  • A.S. Dusso

    Update on the biologic role of vitamin D on the endocrine system

    Curr. Vasc. Pharmacol.

    (2014)
  • A.S. Dusso et al.

    Vitamin D

    Am. J. Physiol. Renal Physiol.

    (2005)
  • M.J. Larriba et al.

    Interaction of vitamin with membrane-based signaling pathways

    Front. Physiol.

    (2014)
  • I.S. Fetahu et al.

    Vitamin D and the epigenome

    Front. Physiol.

    (2014)
  • G.D. King et al.

    Promoter methylation and age-related downregulation of Klotho in rhesus monkey

    Age

    (2011)
  • J. Lee et al.

    Theranti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma

    Mol. Cancer

    (2010)
  • S.D. van Otterdijk et al.

    Do age-related changes in DNA methylation play a role in the development of age-related diseases?

    Biochem. Soc. Trans.

    (2013)
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