J Nutr Health.  2016 Feb;49(1):1-7. 10.4163/jnh.2016.49.1.1.

Vitamin D: Hormone-like nutrient

• Shin MY
• Kwun IS

• KMID: 2158300
• DOI: http://doi.org/10.4163/jnh.2016.49.1.1

Abstract

PURPOSE
The aim of this review is to comprehensively summarize the definition of vitamin D as a nutrient as well as a hormone-like molecule and its new function in prevention of various chronic diseases.
METHODS
The review was written by the method for systematic reivew writing. Literatures from the various sources, including research articles, book chapters, proceedings and electronic materials as appropriate, were screened first and then reviewed and analyzed for the review.
RESULTS
Vitamin D was originally considered as the essential nutrient as a vital carbon compound and was first discovered among children with osteomalacia, also known as ricket disease, characterized by poorly calcified bones which were easily bent rather than broken. Since that time, vitamin D has been known as the key nutrient to improve bone health. However, recently emerging study findings have shown that vitamin D acts as the hormone-like nutrient since it is synthesized like a hormone when our body needs and this particular vitamin also acts like a cell signaling ligand which regulates gene expression of various proteins. So far positive effects of vitamin D have been suggested for the action of anticancer, anti-immune function, and anti-cardiovascular disease, as well as antidiabetic function, etc. In this review, the definition for vitamin D as a nutrient vitamin as well as a hormone-like molecule, cell signaling mechanism of vitamin D, and finally the potential role for the prevention of chronic diseases are discussed.
CONCLUSION
Vitamin D is now being considered as a vital nutrient as a vitamin and as a potential substance for prevention of several chronic diseases.

Keyword

vitamin D; bone health; hormone; chronic disease

MeSH Terms

Books
Carbon
Child
Chronic Disease
Gene Expression
Humans
Osteomalacia
Vitamin A
Vitamin D*
Vitamins*
Writing
Carbon
Vitamin A
Vitamin D
Vitamins

Figure

• 

  Fig. 1 Vitamin D synthesis using sunlight and cholestrol in body. Vitamin D precursor (or called as pro-vitamin D3) is first synthesiszed at skin tissue (skin cells) using sunlight (ultraviolet B, UVB), then this synthesized vitamin D precursor is secreted outside skin cells and carried to the liver through blood vessel and after then in the liver it is transformed to 25(OH)D (cholecalcitriol). Once synthesized, 25(OH)D is secreted outside liver cell and transferred to the kidney and there 25(OH)D is synthesized to 1,25(OH)2D as the final form of active vitamin D. This active form of 1,25(OH)2D is now secreted outside kidney cells and carried to the various tissue where vitamin D activity is needed. Our body only can use vitamin D as the active vitamin D type as 1,25(OH)2D. Abbreviations: UVB - ultraviolet B; vitamin D precursor - previtamin D3 or provitamin D3; 25(OH)D - cholecalcitrol; 1,25(OH) 2D –1,25-dihydrooxycholecalciferol or calcitriol; active vitamin D – 1,25(OH)2D (Image was revised by the authors. Source: Reference 8).

• 

  Fig. 2 The structure of cholesterol and 7-dehydrocholesterol (provitamin D3) (Image was redrawn and revised. Source: References 3 and 8).

• 

  Fig. 3 Types of vitamin D. Vitamin D2 is abundantly present in mushroom, while D3 (25-hydroxy-cholecalciferol) is synthesized to cholesterol at skin. Vitamin D3 is synthesized by adding one OH (hydroxyl) group to the provitamin D at the liver, and then again one more OH group added at the kidney, which finally 1,25-dihydroxycholecalciferol (calcitriol, active form of vitamin D) is synthesized. Our body can utilize vitamin D2 from mushroom etc. to the active form of vitamin D (calcitriol) (Image was redrawn and revised. Source: References 3 and 8).

• 

  Fig. 4 Hormone and hormonal cell signaling. Hormone is the cell signaling protein which is synthesized by the particular endocrine cells. Once hormone is synthesized, then it is secreted outside cells and then travels in blood stream to the hormone target cells. At the target cells, hormone do act as hormonal cell signaling. Vitamin D acts like hormon (hormone-like nutrient), because it is finally synthesized by the kidney cells as the active form of vitamin D (1,25(OH)2 vitamin D, calcitriol), then secreted into the blood stream and carried to various target cells which it works as hormonal cell signaling molecule (Image was revised. Source: Reference 8).

• 

  Fig. 5 Vitamin D synthesis in our body and the pathway to affect on gene expression. Vitamin D, whether it is acquired from the diet or synthesized in our body, is finally syntheized to the active form of 1,25(OH)2D and carried to the target cells via blood vessels. In the cells, vitamin D affects on vitamin D-dependent gene expression and therefore finally protein expression. For example, when our body needs the protein which assists Ca absorption or promotes bone health, then vitamin D can signal these informations. Then vitamin D helps to upregulate those particular genes and proteins expression. When vitamin D stimulates upregulation of gene expression as shown in figure, vitamin D needs to complex with RXR (retinoid X receptor protein) and VDR (vitamin D receptor protein). Therefore nutrient retinol is critical for vitamin D action. Abbreiviation: CYP27A1, cytochrome P450, family 27, subfamily A, polypeptide 1; CYP27B1, cytochrome P450, family 27, subfamily B, polypeptide 1; RXR, retinoid X receptor; VDR, vitamin D (1,25-dihydroxyvitamin D3) receptor; 25(OH)D, 25-hydroxyvitamin D; 1,25(OH)2D, 1,25-dihydroxyvitamin D (Image was revised. Source: Reference 9).

• 

  Fig. 6 Cell signaling and the regulation of protein expression by vitamin D. Active vitamin D (1,25[OH]2 Vit D), which is synthesized by kidney cells and secreted into the blood vessels, combines with vitamin D-binding protein (DBP) in the blood, and then move into the cells which are the target cells of vitamin D. Within the cytosol, vitamin D receptor protein (VDR) can recognize this vitamin D-DBP complex and once vitamin D-DBP complex is detached, then vitamin D combines at this time with VDR to get into the nucleus. Within the nucleus, vitamin D-VDR-RXR complex combines with a particular vitamin D-dependent DNA elements and regulates the vitamin D-dependent gene expression (transcription). Abbreviation: DBP, vitamin D binding protein; 1,25[OH]2 Vit D), active vitamin D; VDR, vitamin D receptor; RXR, retinoid X receptor; DNA, deoxyribonucleic acid; RNA, ribonucleic acid; +/- gene transcription, up-/down-regulation (Image was revised. Source: Reference 6).

• 

  Fig. 7 The nutrient and hormone-like roles of vitamin D. Traditionally, vitamin D is well known as the nutrient which promotes bone health by stimulating Ca absorption by upregulating the protein expresstion and synthesis for Ca absorption and osteoblast differentiation etc (as nutrient). In these days, numerous studies show that vitamin D is also having various functions of anticancer through up-regulating the proteins for preventing cancer cell proliferation, anti-cardiovascular and anti-diabetic function, which are not considered only as the nutrient but cell signaling molecule (hormone-like nutrient). Abbreviations: VDR, vitamine D receptor protein; RXR, retinoid X receptor; RNA POL II, RNA polymerase II; VDRE, vitamin D response element (Image was revised. Source: Reference 22).

Reference

1. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ockene JK, O'Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Stefanick ML, Van Horn L, Wactawski-Wende J, Whitlock E, Anderson GL, Assaf AR, Barad D. Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354(7):669–683.

2. Anderson PH, Atkins GJ. The skeleton as an intracrine organ for vitamin D metabolism. Mol Aspects Med. 2008; 29(6):397–406.

3. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005; 289(1):F8–F28.

4. Khan KS, Kunz R, Kleijnen J, Antes G. Five steps to conducting a systematic review. J R Soc Med. 2003; 96(3):118–121.

5. Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357(3):266–281.

6. Reddy Vanga S, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health. Am J Cardiol. 2010; 106(6):798–805.

7. Davis CD, Milner JA. Nutrigenomics, vitamin D and cancer prevention. J Nutrigenet Nutrigenomics. 2011; 4(1):1–11.

8. Vitamin D and your health: breaking old rules, raising new hopes [Internet]. Boston (MA): Harvard Health Publications;2009. Jun. 9. cited 2015 Nov 10. Available from: http://www.health.harvard.edu/newsweek/vitamin-d-and-your-health.htm.

9. Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, Abnet CC, Huang WY, Kibel AS, Crawford ED, Weinstein SJ, Chanock SJ, Schatzkin A, Hayes RB. Prostate, Lung, Colorectal and Ovarian Trial Project Team. Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk. Carcinogenesis. 2009; 30(5):769–776.

10. Haussler MR, Haussler CA, Whitfield GK, Hsieh JC, Thompson PD, Barthel TK, Bartik L, Egan JB, Wu Y, Kubicek JL, Lowmiller CL, Moffet EW, Forster RE, Jurutka PW. The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging. J Steroid Biochem Mol Biol. 2010; 121(1-2):88–97.

11. Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan C, Ichiyama K, Yoshimura A, Steinman L, Christakos S, Youssef S. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol. 2011; 31(17):3653–3669.

12. Kolek OI, Hines ER, Jones MD, LeSueur LK, Lipko MA, Kiela PR, Collins JF, Haussler MR, Ghishan FK. 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005; 289(6):G1036–G1042.

13. Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013; 92(2):77–98.

14. Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010; 61:91–104.

15. Bikle D. Extrarenal synthesis of 1,25-dihydroxyvitamin D and its health implications. In : Holick MF, editor. Vitamin D: physiology, molecular biology, and clinical applications. 2nd edition. New York (NY): Humana;2010. p. 277–295.

16. Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A. 1992; 89(17):8097–8101.

17. Murillo G, Matusiak D, Benya RV, Mehta RG. Chemopreventive efficacy of 25-hydroxyvitamin D3 in colon cancer. J Steroid Biochem Mol Biol. 2007; 103(3-5):763–767.

18. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008; 8(9):685–698.

19. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab. 2008; 4(2):80–90.

20. Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol. 2009; 4(9):1515–1522.

21. Grundmann M, von Versen-Höynck F. Vitamin D - roles in women's reproductive health? Reprod Biol Endocrinol. 2011; 9:146.

22. UCLA Orthopaedic Surgery (US). Vitamin D and human health [Internet]. Los Angeles (CA): UCLA Heath;cited 2015 Dec 10. Available from: http://ortho.ucla.edu/body.cfm?id=205.