Modern views on the metabolism and biological effects of vitamin D

Authors

DOI:

https://doi.org/10.22141/2224-0721.18.2.2022.1156

Keywords:

vitamin D metabolism, pleiotropic extraskeletal effects, review

Abstract

Vitamin D is a steroid hormone that plays a crucial role in maintaining normal bone condition and calcium homeostasis. In recent years, vitamin D has become a hot topic of endocrinological research, largely Due to the COVID-19 pandemic and the likely correlation between hypovitaminosis D and a high risk of chronic lung disease and associated mortality. Recent studies have shown that vitamin D exhibits a complex multistage metabolism and acts as a hormone on many extracellular targets. This review examines some new intriguing and as yet unclear aspects of vitamin D metabolism, such as new concepts of enzyme regulation, new pleiotropic effects of vitamin D receptor activation (VDR), and epigenetic effects. The mechanisms of vitamin D synthesis in the skin, its metabolism in the hepatic cytochrome P450 system, catabolism, metabolites and transport, gene control and epigenetic modulation are considered in Detail. In addition to the well-known role of vitamin D in calcium and bone metabolism, it has many pleiotropic extraskeletal effects, including potent effects on the immune system, cardiovascular system, adipose tissue and glucose/lipid metabolism, muscle and more. Experimental studies have shown that VDRs are expressed by cancer cell lines. Recent studies have shown a link between low levels of vitamin D and almost all aspects of the metabolic syndrome, such as type 2 diabetes, fasting blood glucose, hypertension, dyslipidemia, obesity and insulin resistance. Several studies have focused on the role of vitamin D in adipose tissue biology. In particular, a negative correlation between vitamin D and leptin or resistin is shown, as well as an inverse correlation with adiponectin. Recent studies in vitamin D-deficient mice have shown impaired secretion of glucose-stimulated insulin by pancreatic islets. Vitamin D is thought to play a role in the pathogenesis and progression of cancer, and vitamin D analogues can slow cancer progression and metastasis. It is concluded that vitamin D is a molecule with several endocrine, paracrine and autocrine effects on many tissues and organs, in addition to maintaining skeletal homeostasis. Research in this area, which aims to clarify the pleiotropy of many effects of vitamin D and its metabolites, continues.

Downloads

Download data is not yet available.

References

Giustina A, Adler RA, Binkley N, et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Rev Endocr Metab Disord. 2020;21(1):89-116. doi: 10.1007/s11154-019-09532-w.

Teshome A, Adane A, Girma B, Mekonnen ZA. The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis. Front Public Health. 2021;9:624559. doi: 10.3389/fpubh.2021.624559.

Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40(4):1109-1151. doi: 10.1210/er.2018-00126.

Saponaro F, Saba A, Zucchi R. An Update on Vitamin D Metabolism. Int J Mol Sci. 2020;21(18):6573. doi: 10.3390/ijms21186573.

Hanel A, Carlberg C. Vitamin D and evolution: Pharmacologic implications. Biochem Pharmacol. 2020;173:113595. doi: 10.1016/j.bcp.2019.07.024.

Wacker M, Holick MF. Sunlight and Vitamin D: A global perspective for health. Dermatoendocrinol. 2013;5(1):51-108. doi: 10.4161/derm.24494.

Mitsche MA, McDonald JG, Hobbs HH, Cohen JC. Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. Elife. 2015 Jun 26;4:e07999. doi: 10.7554/eLife.07999.

Prabhu AV, Luu W, Li D, Sharpe LJ, Brown AJ. DHCR7: A vital enzyme switch between cholesterol and vitamin D production. Prog Lipid Res. 2016;64:138-151. doi: 10.1016/j.plipres.2016.09.003.

Movassaghi M, Bianconi S, Feinn R, Wassif CA, Porter FD. Vitamin D levels in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2017;173(10):2577-2583. doi: 10.1002/ajmg.a.38361.

Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010;19(13):2739-45. doi: 10.1093/hmg/ddq155.

Prabhu AV, Luu W, Sharpe LJ, Brown AJ. Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis. J Biol Chem. 2016;291(16):8363-73. doi: 10.1074/jbc.M115.699546.

Passeron T, Bouillon R, Callender V, et al. Sunscreen photoprotection and vitamin D status. Br J Dermatol. 2019;181(5):916-931. doi: 10.1111/bjd.17992.

Bikle D, Christakos S. New aspects of vitamin D metabolism and action – addressing the skin as source and target. Nat Rev Endocrinol. 2020;16(4):234-252. doi: 10.1038/s41574-019-0312-5.

Khammissa RAG, Fourie J, Motswaledi MH, Ballyram R, Lemmer J, Feller L. The Biological Activities of Vitamin D and Its Receptor in Relation to Calcium and Bone Homeostasis, Cancer, Immune and Cardiovascular Systems, Skin Biology, and Oral Health. Biomed Res Int. 2018;2018:9276380. doi: 10.1155/2018/9276380.

Bikle DD, Jiang Y, Nguyen T, Oda Y, Tu CL. Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. Front Physiol. 2016;7:296. doi: 10.3389/fphys.2016.00296.

Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW. Structural analysis of CYP2R1 in complex with vitamin D3. J Mol Biol. 2008 Jun 27;380(1):95-106. doi: 10.1016/j.jmb.2008.03.065.

Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7711-5. doi: 10.1073/pnas.0402490101.

Duan L, Xue Z, Ji H, Zhang D, Wang Y. Effects of CYP2R1 gene variants on vitamin D levels and status: A systematic review and meta-analysis. Gene. 2018;678:361-369. doi: 10.1016/j.gene.2018.08.056.

Roizen JD, Long C, Casella A, et al. Obesity Decreases Hepatic 25-Hydroxylase Activity Causing Low Serum 25-Hydroxyvitamin D. J Bone Miner Res. 2019;34(6):1068-1073. doi: 10.1002/jbmr.3686.

Roizen JD, Long C, Casella A, et al. Obesity Decreases Hepatic 25-Hydroxylase Activity Causing Low Serum 25-Hydroxyvitamin D. J Bone Miner Res. 2019;34(6):1068-1073. doi: 10.1002/jbmr.3686.

Aatsinki SM, Elkhwanky MS, Kummu O, et al. Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes. Diabetes. 2019;68(5):918-931. doi: 10.2337/db18-1050.

Roizen JD, Li D, O'Lear L, et al. CYP3A4 mutation causes vitamin D-dependent rickets type 3. J Clin Invest. 2018;128(5):1913-1918. doi: 10.1172/JCI98680.

Tsukasaki M, Takayanagi H. Osteoimmunology: evolving concepts in bone-immune interactions in health and disease. Nat Rev Immunol. 2019 Oct;19(10):626-642. doi: 10.1038/s41577-019-0178-8.

Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res. 2014;55(1):13-31. doi: 10.1194/jlr.R031534.

Bikle DD, Patzek S, Wang Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review. Bone Rep. 2018;8:255-267. doi: 10.1016/j.bonr.2018.02.004.

Bouillon R, Bikle D. Vitamin D Metabolism Revised: Fall of Dogmas. J Bone Miner Res. 2019 Nov;34(11):1985-1992. doi: 10.1002/jbmr.3884.

Makris K, Sempos C, Cavalier E. The measurement of vitamin D metabolites: part I-metabolism of vitamin D and the measurement of 25-hydroxyvitamin D. Hormones (Athens). 2020 Jun;19(2):81-96. doi: 10.1007/s42000-019-00169-7.

Volmer DA, Mendes LR, Stokes CS. Analysis of vitamin D metabolic markers by mass spectrometry: current techniques, limitations of the "gold standard" method, and anticipated future directions. Mass Spectrom Rev. 2015;34(1):2-23. doi: 10.1002/mas.21408.

Binkley N, Sempos CT; Vitamin D Standardization Program (VDSP). Standardizing vitamin D assays: the way forward. J Bone Miner Res. 2014;29(8):1709-14. doi: 10.1002/jbmr.2252.

Bouillon R, Schuit F, Antonio L, Rastinejad F. Vitamin D Binding Protein: A Historic Overview. Front Endocrinol (Lausanne). 2020;10:910. doi: 10.3389/fendo.2019.00910.

Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M. Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014;144 Pt A:132-7. doi: 10.1016/j.jsbmb.2013.09.012.

Caprio M, Infante M, Calanchini M, Mammi C, Fabbri A. Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects. Eat Weight Disord. 2017;22(1):27-41. doi: 10.1007/s40519-016-0312-6.

Carlberg C, Molnár F. Vitamin D receptor signaling and its therapeutic implications: Genome-wide and structural view. Can J Physiol Pharmacol. 2015;93(5):311-8. doi: 10.1139/cjpp-2014-0383.

Carlberg C. Nutrigenomics of Vitamin D. Nutrients. 2019;11(3):676. doi: 10.3390/nu11030676.

Maestro MA, Molnár F, Mouriño A, Carlberg C. Vitamin D receptor 2016: novel ligands and structural insights. Expert Opin Ther Pat. 2016 Nov;26(11):1291-1306. doi: 10.1080/13543776.2016.1216547.

Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene. 2015;561(2):171-80. doi: 10.1016/j.gene.2015.02.024.

Pereira F, Barbáchano A, Silva J, et al. KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum Mol Genet. 2011;20(23):4655-65. doi: 10.1093/hmg/ddr399.

Carlberg C. Molecular endocrinology of vitamin D on the epigenome level. Mol Cell Endocrinol. 2017 Sep 15;453:14-21. doi: 10.1016/j.mce.2017.03.016.

Bikle DD. Extraskeletal actions of vitamin D. Ann N Y Acad Sci. 2016;1376(1):29-52. doi: 10.1111/nyas.13219.

Koivisto O, Hanel A, Carlberg C. Key Vitamin D Target Genes with Functions in the Immune System. Nutrients. 2020;12(4):1140. doi: 10.3390/nu12041140.

Martens PJ, Gysemans C, Verstuyf A, Mathieu AC. Vitamin D's Effect on Immune Function. Nutrients. 2020;12(5):1248. doi: 10.3390/nu12051248.

Colotta F, Jansson B, Bonelli F. Modulation of inflammatory and immune responses by vitamin D. J Autoimmun. 2017;85:78-97. doi: 10.1016/j.jaut.2017.07.007.

Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency and community-acquired pneumonia: A meta-analysis of observational studies. Medicine (Baltimore). 2019;98(38):e17252. doi: 10.1097/MD.0000000000017252.

Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi: 10.1136/bmj.i6583.

Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296(23):2832-8. doi: 10.1001/jama.296.23.2832.

Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(5):565-71. doi: 10.1136/jnnp-2011-301876.

Danik JS, Manson JE. Vitamin d and cardiovascular disease. Curr Treat Options Cardiovasc Med. 2012;14(4):414-24. doi: 10.1007/s11936-012-0183-8.

Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol. 2016 Jul;13(7):404-17. doi: 10.1038/nrcardio.2016.73.

Lugg ST, Howells PA, Thickett DR. Optimal Vitamin D Supplementation Levels for Cardiovascular Disease Protection. Dis Markers. 2015;2015:864370. doi: 10.1155/2015/864370.

Muscogiuri G, Nuzzo V, Gatti A, et al. Hypovitaminosis D: a novel risk factor for coronary heart disease in type 2 diabetes? Endocrine. 2016;51(2):268-73. doi: 10.1007/s12020-015-0609-7.

Pankiv VI, Yuzvenko TYu, Pankiv I. Type 2 diabetes mellitus and subclinical hypothyroidism: focusing on the role of cholecalciferol. Problems of Endocrine Pathology. 2019;68(2):46-51. doi: 10.21856/j-PEP.2019.2.07.

Stokić E, Kupusinac A, Tomic-Naglic D, Smiljenic D, Kovacev-Zavisic B, Srdic-Galic B, Soskic S, Isenovic ER. Vitamin D and Dysfunctional Adipose Tissue in Obesity. Angiology. 2015;66(7):613-8. doi: 10.1177/0003319714543512.

Mathieu C. Vitamin D and diabetes: Where do we stand? Diabetes Res Clin Pract. 2015 May;108(2):201-9. doi: 10.1016/j.diabres.2015.01.036.

Bischoff-Ferrari HA. Relevance of vitamin D in muscle health. Rev Endocr Metab Disord. 2012 Mar;13(1):71-7. doi: 10.1007/s11154-011-9200-6.

Colston K, Colston MJ, Feldman D. 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture. Endocrinology. 1981 Mar;108(3):1083-6. doi: 10.1210/endo-108-3-1083.

Duffy MJ, Murray A, Synnott NC, O'Donovan N, Crown J. Vitamin D analogues: Potential use in cancer treatment. Crit Rev Oncol Hematol. 2017;112:190-197. doi: 10.1016/j.critrevonc.2017.02.015.

Published

2022-04-26

How to Cite

Tkach, S., Pankiv, V., & Pankiv, I. (2022). Modern views on the metabolism and biological effects of vitamin D. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), 18(2), 109–117. https://doi.org/10.22141/2224-0721.18.2.2022.1156

Issue

Section

Literature Review

Similar Articles

You may also start an advanced similarity search for this article.

Most read articles by the same author(s)

<< < 2 3 4 5 6 7 8 9 10 11 > >>