Vitamin D

The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1α-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1α-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1α-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.

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Vitamin D Measurement, the Debates Continue, New Analytes Have Emerged, Developments Have Variable Outcomes

Calcified Tissue International ◽

10.1007/s00223-019-00620-2 ◽

2019 ◽

Vol 106 (1) ◽

pp. 3-13 ◽

Cited By ~ 8

Author(s):

William D. Fraser ◽

Jonathan C. Y. Tang ◽

John J. Dutton ◽

Inez Schoenmakers

Keyword(s):

Vitamin D ◽

Quality Assurance ◽

Measurement Procedure ◽

Vitamin D Metabolites ◽

Experimental Conditions ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Target Values ◽

Analytical Approaches

AbstractThe demand for measurement of vitamin D metabolites for clinical diagnosis and to advance our understanding of the role of vitamin D in human health has significantly increased in the last decade. New developments in technologies employed have enabled the separation and quantification of additional metabolites and interferences. Also, developments of immunoassays have changed the landscape. Programmes and materials for assay standardisation, harmonisation and the expansion of the vitamin D external quality assurance scheme (DEQAS) with the provision of target values as measured by a reference measurement procedure have improved standardisation, quality assurance and comparability of measurements. In this article, we describe developments in the measurement of the commonly analysed vitamin D metabolites in clinical and research practice. We describe current analytical approaches, discuss differences between assays, their origin, and how these may be influenced by physiological and experimental conditions. The value of measuring metabolites beyond 25 hydroxyvitamin D (25(OH)D), the marker of vitamin D status, in routine clinical practice is not yet confirmed. Here we provide an overview of the value and application of the measurement of 1,25 dihydroxyvitamin D, 24,25 dihydroxyvitamin D and free 25OHD in the diagnosis of patients with abnormalities in vitamin D metabolism and for research purposes.

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Early-Life Effects of Vitamin D: A Focus on Pregnancy and Lactation

Annals of Nutrition and Metabolism ◽

10.1159/000508422 ◽

2020 ◽

Vol 76 (2) ◽

pp. 16-28

Author(s):

Carol L. Wagner ◽

Bruce W. Hollis

Keyword(s):

Vitamin D ◽

Vitamin D Supplementation ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Breastfed Infants ◽

Intention To Treat ◽

Pregnancy And Lactation ◽

Maternal Supplementation ◽

Relative Deficiency

Vitamin D is an endocrine regulator of calcium and bone metabolism. Yet, its effects include other systems, such as innate and adaptive immunity. Unique to pregnancy, circulating 1,25-dihydroxyvitamin D (1,25[OH]2D) increases early on to concentrations that are 2–3 times prepregnant values. At no other time during the lifecycle is the conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25(OH)2D directly related and optimized at ≥100 nmol/L. Vitamin D deficiency appears to affect pregnancy outcomes, yet randomized controlled trials of vitamin D supplementation achieve mixed results depending on when supplementation is initiated during pregnancy, the dose and dosing interval, and the degree of deficiency at the onset of pregnancy. Analysis of trials on an intention-to-treat basis as opposed to the use of 25(OH)D as the intermediary biomarker of vitamin D metabolism yields differing results, with treatment effects often noted only in the most deficient women. Immediately after delivery, maternal circulating 1,25(OH)2D concentrations return to prepregnancy baseline, at a time when a breastfeeding woman has increased demands of calcium, beyond what was needed during the last trimester of pregnancy, making one question why 1,25(OH)2D increases so significantly during pregnancy. Is it to serve as an immune modulator? The vitamin D content of mother’s milk is directly related to maternal vitamin D status, and if a woman was deficient during pregnancy, her milk will be deficient unless she is taking higher doses of vitamin D. Because of this relative “deficiency,” there is a recommendation that all breastfed infants receive 400 IU vitamin D3/day starting a few days after birth. The alternative – maternal supplementation with 6,400 IU vitamin D3/day, effective in safely raising maternal circulating vitamin D, that of her breast milk, and effective in achieving sufficiency in her recipient breastfeeding infant – remains a viable option. Additional research is needed to understand vitamin D’s influence on pregnancy health and the effect of maternal supplementation on breast milk’s immune signaling.

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Metabolism of 25-hydroxyvitamin D in copper-laden rat: a model of Wilson's disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1988.254.2.e150 ◽

1988 ◽

Vol 254 (2) ◽

pp. E150-E154

Author(s):

T. O. Carpenter ◽

M. L. Pendrak ◽

C. S. Anast

Keyword(s):

Vitamin D ◽

Wilson’S Disease ◽

Wilson's Disease ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Hepatic Copper ◽

25 Hydroxyvitamin D ◽

Potential Factor

Wilson's disease results in excess tissue accumulation of copper and is often complicated by skeletal and mineral abnormalities. We investigated vitamin D metabolism in rats fed a copper-laden diet rendering hepatic copper content comparable with that found in Wilson's disease. Injection of 25-hydroxyvitamin D3 [25(OH)D3] resulted in reduced 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in copper-intoxicated rats. In vitro 25(OH)D-1 alpha-hydroxylase activity was impaired in renal mitochondria from copper-intoxicated animals. Activity was also inhibited in mitochondria from controls when copper was added to incubation media. Impaired conversion of 25(OH)D to 1,25(OH)2D occurs in copper intoxication and suggests that altered vitamin D metabolism is a potential factor in the development of bone and mineral abnormalities in Wilson's disease.

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Association of Differing Qatari Genotypes with Vitamin D Metabolites

International Journal of Endocrinology ◽

10.1155/2020/7831590 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Youssra Dakroury ◽

Alexandra E. Butler ◽

Soha R. Dargham ◽

Aishah Latif ◽

Amal Robay ◽

...

Keyword(s):

Vitamin D ◽

Skin Pigmentation ◽

Genetic Differences ◽

Vitamin D Metabolites ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Increased Risk ◽

25 Hydroxyvitamin D

Objective. Genetic studies have identified four Qatari genotypes: Q1 Arab, Bedouin; Q2 Asian/Persian; Q3 African; and a fourth admixed group not fitting into the previous 3 groups. This study was undertaken to determine if there was an increased risk of deficiency of vitamin D and its metabolites associated with differing genotypes, perhaps due to genetic differences in skin pigmentation. Methods. 398 Qatari subjects (220 type 2 diabetes and 178 controls) had their genotype determined by Affymetrix 500 k SNP arrays. Total values of 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 25-hydroxy-3epi-vitamin D (3epi-25(OH)D) concentrations were measured by the LC-MS/MS analysis. Results. The distribution was as follows: 164 (41.2%) genotyped Q1, 149 (37.4%) genotyped Q2, 31 (7.8%) genotyped Q3, and 54 (13.6%) genotyped “admixed.” Median levels of 25(OH)D and 3epi-25(OH)D did not differ across Q1, Q2, Q3, and “admixed” genotypes, respectively. 1,25(OH)2D levels were lower (p<0.04) between Q2 and the admixed groups, and 24,25(OH)2D levels were lower (p<0.05) between Q1 and the admixed groups. Vitamin D metabolite levels were lower in females for 25(OH)D, 1,25(OH)2D (p<0.001), and 24,25(OH)2D (p<0.006), but 3epi-25(OH)D did not differ (p<0.26). Diabetes prevalence was not different between genotypes. Total 1,25(OH)2D (p<0.001), total 24,25(OH)2D (p<0.001), and total 3epi-25(OH)D (p<0.005) were all significantly lower in diabetes patients compared to controls whilst the total 25(OH)D was higher in diabetes than controls (p<0.001). Conclusion. Whilst 25(OH)D levels did not differ between genotype groups, 1,25(OH)2D and 24,25(OH)2D were lower in the admixed group, suggesting that there are genetic differences in vitamin D metabolism that may be of importance in a population that may allow a more targeted approach to vitamin D replacement. This may be of specific importance in vitamin D replacement strategies with the Q2 genotype requiring less, and the other genotypes requiring more to increase 1,25(OH)2D. Whilst overall the group was vitamin D deficient, total 25(OH)D was higher in diabetes, but 1,25(OH)2D, 24,25(OH)2D, and 3epi-25(OH)D were lower in diabetes that did not affect the relationship to genotype.

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Simple Fast Quantification of Cholecalciferol, 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D in Adipose Tissue Using LC-HRMS/MS

Nutrients ◽

10.3390/nu11091977 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1977 ◽

Cited By ~ 3

Author(s):

Laurianne Bonnet ◽

Marielle Margier ◽

Ljubica Svilar ◽

Charlene Couturier ◽

Emmanuelle Reboul ◽

...

Keyword(s):

Vitamin D ◽

Adipose Tissue ◽

Solid Phase ◽

Vitamin D Metabolites ◽

Vitamin D Metabolism ◽

Dihydroxyvitamin D3 ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Relative Standard ◽

The Impact

Vitamin D metabolism is actively modulated in adipose tissue during obesity. To better investigate this process, we develop a specific LC-HRMS/MS method that can simultaneously quantify three vitamin D metabolites, i.e., cholecalciferol, 25-hydroxyvitamin D3 (25(OH)D3), and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in a complex matrix, such as mouse adipose tissue and plasma. The method uses pretreatment with liquid–liquid or solid–phase extraction followed by derivatization using Amplifex® reagents to improve metabolite stability and ionization efficiency. Here, the method is optimized by co-eluting stable isotope-labelled internal standards to calibrate each analogue and to spike biological samples. Intra-day and inter-day relative standard deviations were 0.8–6.0% and 2.0–14.4%, respectively for the three derivatized metabolites. The limits of quantification (LoQ) achieved with Amplifex® derivatization were 0.02 ng/mL, 0.19 ng/mL, and 0.78 ng/mL for 1,25(OH)2D3, 25(OH)D3 and cholecalciferol, respectively. Now, for the first time, 1,25(OH)2D3 can be co-quantified with cholecalciferol and 25(OH)D3 in mouse adipose tissue. This validated method is successfully applied to study the impact of obesity on vitamin D status in mice.

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Reshaping the way we view vitamin D signalling and the role of vitamin D in health

Nutrition Research Reviews ◽

10.1079/nrr200480 ◽

2004 ◽

Vol 17 (2) ◽

pp. 241-248 ◽

Cited By ~ 4

Author(s):

James C. Fleet ◽

Jie Hong ◽

Zhentao Zhang

Keyword(s):

Vitamin D ◽

Transcriptional Activation ◽

Mode Of Action ◽

Uv Light ◽

Active Form ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Molecular Mode

AbstractAlthough the biological requirement for vitamin D can be met by epidermal exposure to UV light, there are a number of conditions where this production does not occur or is not sufficient to meet biological needs. When this happens, vitamin D must be consumed and is a nutrient. However, two distinct observations have caused researchers to rethink certain dogma in vitamin D biology. First, it appears that in addition to the hormonally active form of 1,25 dihydroxyvitamin D (1,25(OH)2D), circulating levels of 25 hydroxyvitamin D have a critical importance for optimal human health. This and other data suggest that extra-renal production of 1,25(OH)2D contributes to Ca homeostasis and cancer prevention. Second, in addition to its role in the transcriptional activation of genes through the vitamin D receptor there is now compelling evidence that 1,25(OH)2D has a second molecular mode of action; the rapid activation of second-messenger and kinase pathways. The purpose of this second mode of action is only now being explored. The present review will discuss how these two areas are reshaping our understanding of vitamin D metabolism and action.

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Vitamin D3 metabolism in a pig strain with pseudo vitamin D-deficiency rickets, type I

Acta Endocrinologica ◽

10.1530/acta.0.1150345 ◽

1987 ◽

Vol 115 (3) ◽

pp. 345-352 ◽

Cited By ~ 13

Author(s):

Reinhard Kaune ◽

Johein Harmeyer

Keyword(s):

Vitamin D ◽

Vitamin D Deficiency ◽

Type I ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Before And After ◽

25 Hydroxyvitamin D ◽

Deficiency Rickets ◽

Clinical Healing

Abstract. Vitamin D metabolism was studied in the 'Hannover Pig', a strain which suffers from pseudo vitamin D-deficiency rickets, type I. Animals of this strain are known to be devoid of renal 25-hydroxyvitamin D3-1α-hydroxylase and -24-hydroxylase activities. Pigs with florid rickets and hypocalcaemia were treated with single im injections of 0.25 to 1.25 mg of vitamin D3, doses that have been shown in previous studies to be effective in producing transient healing of rachitic symptoms. The levels of vitamin D3 and its most relevant physiological metabolites in plasma were estimated at intervals before and after this vitamin D3 treatment. Vitamin D3 rose from 14.8 ± 8.1 to 364 ± 190 nmol/l (mean ± sd) 2 to 3 days post injectionem, 25-hydroxyvitamin D3 from 131.0 ± 46.2 to 1068 ± 160 nmol/l within 7 days post injectionem. The 1α,25-dihydroxyvitamin D3 concentration in plasma was elevated from 73.9 ± 25.0 to 281 ± 168 pmol/l 2 to 3 days post injectionem and declined continually from that time. 24R,25-dihydroxyvitamin D3 and 25S,26-dihydroxyvitamin D3 levels after treatment showed different responses in different animals being either elevated or unchanged. Clinical healing of the pigs with these doses of vitamin D3 was attributed to the transient rise of 1α,25-dihydroxyvitamin D3 in plasma. It was assumed that 1α,25-dihydroxyvitamin D3 synthesis takes place under these circumstances in extrarenal tissues.

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Combined Treatment with Omega-3 Fatty Acid and Cholecalciferol Increases 1,25-Dihydroxyvitamin D Levels by Modulating Dysregulation of Vitamin D Metabolism in 5/6 Nephrectomy Rats

Nutrients ◽

10.3390/nu11122903 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2903

Author(s):

Su Mi Lee ◽

Mi Hwa Lee ◽

Young Ki Son ◽

Seong Eun Kim ◽

Won Suk An

Keyword(s):

Vitamin D ◽

Fatty Acid ◽

Combined Treatment ◽

Omega 3 ◽

Sprague Dawley ◽

Vitamin D Metabolism ◽

Omega 3 Fatty Acid ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

The protein 1α-hydroxylase (CYP27B1) was expressed in liver and omega-3 fatty acid (FA) elevated 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in dialysis patients. The aim of this study was to determine whether omega-3 FA and cholecalciferol have effects on vitamin D metabolism related to CYP27B1 and 24-hydroxylase (CYP24) activities in the kidney and liver of 5/6 nephrectomy (Nx) rats. Male Sprague–Dawley rats were divided into the following groups: sham control, 5/6 Nx, 5/6 Nx treated with cholecalciferol, 5/6 Nx treated with omega-3 FA, and 5/6 Nx treated with cholecalciferol/omega-3 FA. CYP27B1 and CYP24 expression were measured in the liver and kidney. Further, 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] levels were measured in serum. Among Nx groups, 1,25(OH)2D and 25(OH)D levels were lowest in the 5/6 Nx group. CYP24 expression was increased in the kidney of the 5/6 Nx rat model, which was found to be reversed by omega-3 FA or cholecalciferol/omega-3 FA supplementation. Decreased CYP27B1 expression was observed in the liver of the 5/6 Nx rats and its expression was recovered by supplementation with cholecalciferol/omega-3 FA. In conclusion, omega-3 FA and cholecalciferol may synergistically increase 1,25(OH)2D levels by inhibiting CYP24 expression in the kidney and liver and activating CYP27B1 expression in the liver of 5/6 Nx rats.

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Vitamin D metabolism in the Damara mole-rat is altered by exposure to sunlight yet mineral metabolism is unaffected

Journal of Endocrinology ◽

10.1677/joe.0.1430367 ◽

1994 ◽

Vol 143 (2) ◽

pp. 367-374 ◽

Cited By ~ 6

Author(s):

T Pitcher ◽

I N Sergeev ◽

R Buffenstein

Keyword(s):

Vitamin D ◽

Mineral Metabolism ◽

Plasma Concentrations ◽

Sun Exposure ◽

Inorganic Phosphorus ◽

Vitamin D Metabolites ◽

Vitamin D Metabolism ◽

Hydroxyvitamin D ◽

Dihydroxyvitamin D ◽

Highly Efficient

Abstract Vitamin D may be endogenously synthezised in the skin in the presence of sunlight or, alternatively, acquired from dietary sources. Cryptomys damarensis appear to have a naturally impoverished vitamin D status with low plasma concentrations of both 25-hydroxyvitamin D (25(OH)D; <5 ng/ml) and 1,25-dihydroxyvitamin D (1,25(OH)2D; <20 pg/ml). We attribute this to their underground habitat and herbivorous habits. We questioned whether these subterranean mammals could utilize sunlight-mediated pathways and therefore compared vitamin D metabolism and function when animals were (a) housed naturally (control), (b) given an oral vitamin D3 (D3) supplement (1 IU/g dry matter food eaten per day) and (c) exposed to 10 h of sunlight. Control animals exhibited a highly efficient apparent fractional absorption of both calcium (Ca) and inorganic phosphorus (Pi) (>90%), passive mode of intestinal mineral uptake, yet tightly regulated serum ionized calcium (Ca2+). The ratio of 25(OH)D-1α-hydroxylase (1-OHase) to 25(OH)D-24R-hydroxylase (24-OHase) activity in the kidney, corresponded with a state of vitamin D deficiency. Cryptomys damarensis responded to both oral D3 supplementation and sun exposure by an increase in plasma concentration of 1,25(OH)2D with a commensurate decline (P<0·05) in 1-OHase activity, and a resulting decrease (P<0·05) in the ratio of 1-OHase:24-OHase activity. Despite these changes, the intestinal mode of Ca uptake and plasma total Ca, Ca2+ and Pi remained unchanged with either treatment. Responses to sunlight were less pronounced than that of oral D3 supplementation. These data confirm that naturally vitamin D-deficient mole-rats can convert vitamin D to the active hormone 1,25(OH)2D, and indicate that mole-rats function optimally at the low concentrations of vitamin D metabolites found naturally. Furthermore, these animals exhibit a highly efficient vitamin D-independent mode of intestinal Ca absorption. Journal of Endocrinology (1994) 143, 367–374

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Effect of Parathyroid Hormone on Vitamin D Metabolism in Osteopetrosis

PEDIATRICS ◽

10.1542/peds.68.1.109 ◽

1981 ◽

Vol 68 (1) ◽

pp. 109-112

Author(s):

Dagfinn Aarskog ◽

Lage Aksnes ◽

Trond Markestad

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Serum Levels ◽

Target Cells ◽

Normal Range ◽

Vitamin D Metabolism ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D ◽

Basal Serum ◽

Parathyroid Extract

Indices of vitamin D metabolism were studied before and after infusion of bovine parathyroid hormone extract in three children with osteopetrosis. Basal serum concentrations of calcium, alkaline phosphatase, and 25-hydroxyvitamin D tended to be low. Serum immunoreactive parathyroid hormone levels were in the upper normal range in two patients. A marked increase in urinary cyclic adenosine 3': 5'-monophosphate(cAMP) in all patients was solely due to an increase in the nephrogenous cAMP. The basal concentration of 1,25-dihydroxyvitamin D was clearly more than the upper limit of normal range in all three patients and increased after parathyroid extract infusion in one patient. The basal serum levels of 24,25-dihydroxyvitamin D were within normal limits and tended to decrease after parathyroid extract infusion in two of the patients. Parathyroid hormone and 1,25-dihydroxyvitamin D act in concert to increase calcium resorption from bone, and the increased serum levels of both these factors may reflect lack, or unresponsiveness, of target cells in bone.

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