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Shanmugasundaram, R., and R. K. Selvaraj. "Vitamin D-1α-hydroxylase and vitamin D-24-hydroxylase mRNA studies in chickens." Poultry Science 91, no. 8 (August 2012): 1819–24. http://dx.doi.org/10.3382/ps.2011-02129.
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Rahmaniyan, Mehrdad, Kennerly Patrick, and Norman H. Bell. "Characterization of recombinant CYP2C11: a vitamin D 25-hydroxylase and 24-hydroxylase." American Journal of Physiology-Endocrinology and Metabolism 288, no. 4 (April 2005): E753—E760. http://dx.doi.org/10.1152/ajpendo.00201.2004.
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Studies were performed to further characterize the male-specific hepatic recombinant microsomal vitamin D 25-hydroxlase CYP2C11, expressed in baculovirus-infected insect cells, and determine whether it is also a vitamin D 24-hydroxylase. 25- and 24-hydroxylase activities were compared with those of 10 other recombinant hepatic microsomal cytochrome P-450 enzymes expressed in baculovirus-infected insect cells. Each of them 25-hydroxylated vitamin D2, vitamin D3, 1α-hydroxyvitamin D2(1αOHD2), and 1α-hydroxyvitamin D3(1αOHD3). CYP2C11 had the greatest activity with these substrates, except vitamin D3, which had the same activity as four of the other enzymes. The descending order of 25-hydroxylation by CYP2C11 was 1αOHD3> 1αOHD2> vitamin D2> vitamin D3. Each of the recombinant cytochrome P-450 enzymes 24-hydroxylated 1αOHD2. CYP2C11 had the greatest activity. 24-Hydroxylation of 1αOHD3was very low, and there was none with vitamin D3. Only CYP2C11 24-hydroxylated vitamin D2. Structures of vitamin D metabolites, including 24-hydroxyvitamin D2, 1,24( S)-dihydroxyvitamin D2, and 1,24-dihydroxyvitamin D3, were confirmed by HPLC and gas chromatography retention times and characteristic mass spectrometric fragmentation patterns. In male rats, hypophysectomy significantly reduced body weight, liver weight, hepatic CYP2C11 mRNA expression, and 24- and 25-hydroxylation of 1αOHD2. Expression of CYP2J3 and CYP2R1 mRNA did not change. In male rat hepatocytes, CYP2C11 mRNA expression and 24- and 25-hydroxylation were significantly reduced after culture for 24 h compared with uncultured cells. Expression of CYP2J3 and CYP2R1 either increased or did not change. It is concluded that CYP2C11 is a male-specific hepatic microsomal vitamin D 25-hydroxylase that hydroxylates vitamin D2, vitamin D3, 1αOHD2, and 1αOHD3. CYP2C11 is also a vitamin D 24-hydroxylase.
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Ren, Songyang, Lisa Nguyen, Shaoxing Wu, Carlos Encinas, John S. Adams, and Martin Hewison. "Alternative Splicing of Vitamin D-24-Hydroxylase." Journal of Biological Chemistry 280, no. 21 (March 23, 2005): 20604–11. http://dx.doi.org/10.1074/jbc.m414522200.
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Warner, M., and A. Tenenhouse. "Regulation of renal vitamin D hydroxylase activity in vitamin D deficient rats." Canadian Journal of Physiology and Pharmacology 63, no. 8 (August 1, 1985): 978–82. http://dx.doi.org/10.1139/y85-161.
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The regulation of renal mitochondrial 1-hydroxylase activity in chronic vitamin D deficiency was studied in male rats. These rats were born of mothers who had been raised from weaning (21 days) on a vitamin D deficient diet and who had no detectable serum 1,25-dihydroxycholecalciferol (1,25-(OH)2D) at the time their offspring were weaned (28 days). In the pups, renal mitochondrial 1-hydroxylase activity was undetectable before the 3rd week of life even though the animals were severely hypocalcemic from birth. The 1-hydroxylase activity first became detectable at 26 days of age, rapidly reached a maximum at day 34, then decreased to become undetectable again by 65 days. Throughout this time serum calcium concentration was <5.0 mg/dL and serum parathyroid hormone (PTH) concentration, measured by a midmolecule radioimmunoassay, was two-to five-fold greater than that found in vitamin D replete rats. 1-Hydroxylase activity could be restored in the +65-day-old animals by administration of a single dose of 2.5 μg vitamin D3. Enzyme activity was detected within 24 h, was maximal at 72 h, and returned to undetectable levels by 96 h after administration of the vitamin. Serum 1,25-(OH)2D which was undetectable before administration of the vitamin D3, was 108 and 458 pg/mL at 16 and 40 h, respectively, after the injection. The serum concentration of this metabolite then decreased progressively to 80 pg/mL by 6 days. 24-Hydroxylase activity first became detectable 48 h after vitamin D administration, increased to a maximum at 96 h, and thereafter decreased to become undetectable by 7 days. The urinary excretion of phosphate and cyclic AMP was 10% of control values between 65 and 90 days of age. These values became normal 4 days after a single dose of 2.5 μg vitamin D3. From these data it is concluded that there are two distinct levels of regulation of 1-hydroxylase activity: a vitamin D independent induction of the activity at the time of weaning that is transient and is not associated with any detectable 24-hydroxylase activity; and the second is a vitamin D dependent induction of enzyme activity seen in animals which prior to administration of the vitamin manifest the characteristics of PTH resistance and have no detectable renal hydroxylase activity. The mechanisms of these effects remain to be determined.
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Akeno, N., A. Matsunuma, T. Maeda, T. Kawane, and N. Horiuchi. "Regulation of vitamin D-1alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney." Journal of Endocrinology 164, no. 3 (March 1, 2000): 339–48. http://dx.doi.org/10.1677/joe.0.1640339.
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We investigated the effects of dexamethasone on vitamin D-1alpha-hydroxylase and -24-hydroxylase expression and on vitamin D receptor (VDR) content in the kidneys of mice fed either a normal (NCD) diet or a calcium- and vitamin D-deficient (LCD) diet for 2 weeks. For the last 5 days mice received either vehicle or dexamethasone (2 mg/kg per day s.c.). Dexamethasone significantly increased plasma calcium concentrations without changing plasma concentrations of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) in both NCD and LCD groups. Northern blot and enzyme activity analyses in NCD mice revealed that dexamethasone increased renal VDR mRNA expression modestly and greatly increased 24-hydroxylase mRNA abundance and enzyme activity, but did not affect 1alpha-hydroxylase mRNA abundance and enzyme activity. In mice fed an LCD diet, dexamethasone increased renal VDR mRNA expression 1.5-fold, decreased 1alpha-hydroxylase mRNA abundance (52%) and activity (34%), and markedly increased 24-hydroxylase mRNA abundance (16-fold) and enzyme activity (9-fold). Dexamethasone treatment did not alter functional VDR number (B(max) 125-141 fmol/mg protein) or ligand affinity (K(d) 0.13-0.10 nM) in LCD mice. Subcutaneous injections of 1,25(OH)(2)D(3) (0.24 nmol/kg per day for 5 days) into NCD mice strongly increased renal 24-hydroxylase mRNA abundance and enzyme activity, while there was no effect of dexamethasone on renal 24-hydroxylase expression in these mice. This may be due to overwhelming induction of 24-hydroxylase by 1,25(OH)(2)D(3). These findings suggest that glucocorticoid-induced osteoporosis is caused by direct action of the steroids on bone, and the regulatory effect of glucocorticoids on renal 25-hydroxyvitamin D(3) metabolism may be less implicated in the initiation and progression of the disease.
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Agu, Chinyere, Ei Cho, Christine Resta, and Rakhlin Luba. "LBSAT130 Hypercalcemia In Pregnancy Due To CYP24A1 Mutation." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A149. http://dx.doi.org/10.1210/jendso/bvac150.303.
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Abstract Background The active form of vitamin D (1,25 OH2 vitamin D) is catabolized by a key enzyme 1,25 OH vitamin D-24 hydroxylase, which is encoded by the CYP24A1 gene. Loss of function mutation in the CYP24A1 leads to elevated levels of active vitamin D, causing PTH independent hypercalcemia with nephrolithiasis and nephrocalcinosis. Two phenotypic variants have been identified: idiopathic infantile hypercalcemia, which is a more severe form presenting in infancy, and a milder form with onset in adulthood as is this case. Pregnancy is known to initiate or worsen the hypercalcemia. Clinical Case A 27-year-old woman presented at 11 weeks gestation with hyperemesis, noted to have hypercalcemia calcium 15.7mg/dl (8.2 to 10.1 pg/ml), low PTH 2pg/ml (24 -85 pg/ml) with high serum 1,25 OHD 309pg/ml (nl 19.9-79.3 pg/ml). She had low PTHrp, normal ACE level, and negative TB testing. Pre-pregnancy calcium was normal (9.8mg/dl). She had a history of hypercalcemia in previous pregnancy (Calcium 13mg/dl) that ended in IUFD. Family history revealed nephrolithiasis in her sister, mother, and paternal aunt as well as a consanguineous marriage in our patient and her parents. Vitamin D metabolites evaluated via liquid chromatography showed low serum 24,25(OH)2D (0.29ng/ml nl N/A) and elevated 25OHD 138 ng/mL (20-80 ng/ml). Ratio of 25 (OH) Vit D to 24,25(OH)2D was 475.86 (values >80 indicate probable bi-allelic CYP24A1 deletion or mutation. Genetic test pending. Conclusion This case highlights the fact that patients with 24 hydroxylase deficiency may be normocalcemic with hypercalcemia unveiled during pregnancy due to increased 1alpha hydroxylase production by the placenta and kidneys as well as intake of prenatal vitamins containing calciferol. An index of suspicion for CYP24A1 mutation is needed in patients with high active vitamin D metabolites, high or normal calcium, low PTH, family history of kidney stones or worsening hypercalcemia in pregnancy. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.
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Lee, Sang R., Mi-Young Park, Hyun Yang, Geun-Shik Lee, Beum-Soo An, Bae-kuen Park, Eui-Bae Jeung, and Eui-Ju Hong. "5α-dihydrotestosterone reduces renal Cyp24a1 expression via suppression of progesterone receptor." Journal of Molecular Endocrinology 60, no. 2 (February 2018): 159–70. http://dx.doi.org/10.1530/jme-17-0187.
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Androgens act in concert with vitamin D to influence reabsorption of calcium. However, it is unclear whether androgens directly regulate vitamin D homeostasis or control other cellular events that are related to vitamin D metabolism. To examine whether the expression of vitamin D-related genes in mouse kidney is driven by androgens or androgen-dependent effects, the androgen receptor and other sex steroid receptors were monitored in orchidectomized mice treated with 5α-dihydrotestosterone (DHT). Our results revealed that exposing orchidectomized mice to DHT inhibited the expression of progesterone receptor (Pgr) with or without estrogen receptor α expression, the latter was confirmed by ER-positive (MCF7 and T47D) or -negative (PCT) cells analysis. The loss of Pgr in turn decreased the expression of renal 24-hydroxylase via transcriptional regulation because Cyp24a1 gene has a progesterone receptor-binding site on promoter. When male kidneys preferentially hydroxylate 25-hydroxyvitamin D3 using 24-hydroxylase rather than 25-hydroxyvitamin D3-1-alpha hydroxylase, DHT suppressed the Pgr-mediated 24-hydroxylase expression, and it is important to note that DHT increased the blood 25-hydroxyvitamin D3 levels. These findings uncover an important link between androgens and vitamin D homeostasis and suggest that therapeutic modulation of Pgr may be used to treat vitamin D deficiency and related disorders.
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Mata-Greenwood, Eugenia, Hans C. A. Westenburg, Stacy Zamudio, Nicholas P. Illsley, and Lubo Zhang. "Decreased Vitamin D Levels and Altered Placental Vitamin D Gene Expression at High Altitude: Role of Genetic Ancestry." International Journal of Molecular Sciences 24, no. 4 (February 8, 2023): 3389. http://dx.doi.org/10.3390/ijms24043389.
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High-altitude hypoxia challenges reproduction; particularly in non-native populations. Although high-altitude residence is associated with vitamin D deficiency, the homeostasis and metabolism of vitamin D in natives and migrants remain unknown. We report that high altitude (3600 m residence) negatively impacted vitamin D levels, with the high-altitude Andeans having the lowest 25-OH-D levels and the high-altitude Europeans having the lowest 1α,25-(OH)2-D levels. There was a significant interaction of genetic ancestry with altitude in the ratio of 1α,25-(OH)2-D to 25-OH-D; with the ratio being significantly lower in Europeans compared to Andeans living at high altitude. Placental gene expression accounted for as much as 50% of circulating vitamin D levels, with CYP2R1 (25-hydroxylase), CYP27B1 (1α-hydroxylase), CYP24A1 (24-hydroxylase), and LRP2 (megalin) as the major determinants of vitamin D levels. High-altitude residents had a greater correlation between circulating vitamin D levels and placental gene expression than low-altitude residents. Placental 7-dehydrocholesterol reductase and vitamin D receptor were upregulated at high altitude in both genetic-ancestry groups, while megalin and 24-hydroxylase were upregulated only in Europeans. Given that vitamin D deficiency and decreased 1α,25-(OH)2-D to 25-OH-D ratios are associated with pregnancy complications, our data support a role for high-altitude-induced vitamin D dysregulation impacting reproductive outcomes, particularly in migrants.
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Buffenstein, R., I. N. Sergeev, and J. M. Pettifor. "Vitamin D hydroxylases and their regulation in a naturally vitamin D-deficient subterranean mammal, the naked mole rat (Heterocephalus glaber)." Journal of Endocrinology 138, no. 1 (July 1993): 59–64. http://dx.doi.org/10.1677/joe.0.1380059.
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ABSTRACT The vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is generated by a series of hydroxylation steps in the liver and kidneys. We investigated whether naturally vitamin D-deficient subterranean mammals (naked mole rats, Heterocephalus glaber) employ the same enzymatic pathways, and whether these are regulated in a similar manner to that established for other mammals. Vitamin D3-25-hydroxylase in the liver and both 25-hydroxyvitamin D3-l-hydroxylase and 25-hydroxyvitamin D3-24 hydroxylase (1-OHase and 24-OHase) in the kidney were detectable in mole rats. As expected for vitamin D-deficient mammals, the 1-OHase activity predominated over the 24-OHase. After mole rats received a supraphysiological supplement of vitamin D3, 1-OHase activity was suppressed and 24-OHase activity was enhanced. Irrespective of vitamin D status, forskolin (a protein kinase A activator) and dibutyryl cyclic AMP did not alter the activity of either 1-OHase or 24-OHase. These findings suggest that the response of renal hydroxylases to parathyroid hormone was blunted. Phorbol esters, 12-O-tetradecanoylphorbol 13-acetate (TPA) and 1-oleoyl-2-acetylglycerol (OAG) (protein kinase C activators), suppressed 1-OHase activity. 24-OHase activity was induced by TPA but not by OAG. These effects were similar to those illicited by vitamin D3 supplementation but were additive in that they increased the responses shown in vitamin D-replete mole rats. These data confirm that naturally vitamin D-deficient mole rats can convert vitamin D3 to the hormone, 1,25(OH)2D3. Furthermore, the enzymes 1-OHase and 24-OHase present in the kidneys of these mammals are regulated independently by 1,25(OH)2D3 and protein kinase C-mediated pathways of intracellular signalling, but are not regulated by the cyclic AMP–protein kinase A signal transduction pathway. Journal of Endocrinology (1993) 138, 59–64
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Agic, Admir, Hong Xu, Christopher Altgassen, Frank Noack, Monika M. Wolfler, Klaus Diedrich, Michael Friedrich, Robert N. Taylor, and Daniela Hornung. "Relative Expression of 1,25-Dihydroxyvitamin D3 Receptor, Vitamin D 1α-Hydroxylase, Vitamin D 24-Hydroxylase, and Vitamin D 25-Hydroxylase in Endometriosis and Gynecologic Cancers." Reproductive Sciences 14, no. 5 (July 2007): 486–97. http://dx.doi.org/10.1177/1933719107304565.
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Miller, Walter L., and Erik A. Imel. "Rickets, Vitamin D, and Ca/P Metabolism." Hormone Research in Paediatrics 95, no. 6 (2022): 579–92. http://dx.doi.org/10.1159/000527011.
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Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D<sub>2</sub> and D<sub>3</sub>, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]<sub>2</sub>D<sub>3</sub>) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative <i>PHEX</i> gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.
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Yamagata, Masayo, Akihito Kimoto, Toshimi Michigami, Masahiro Nakayama, and Keiichi Ozono. "Hydroxylases Involved in Vitamin D Metabolism Are Differentially Expressed in Murine Embryonic Kidney: Application of Whole Mount in Situ Hybridization*." Endocrinology 142, no. 7 (July 1, 2001): 3223–30. http://dx.doi.org/10.1210/endo.142.7.8122.
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Abstract In this study we examined the expression of 25-hydroxyvitamin D-1α-hydroxylase (1α-hydroxylase) and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by RT-PCR and whole mount in situ hybridization using organ culture of kidney taken from mouse embryo. First, the kidneys of mouse embryo at 11.5–17.5 days gestation were cultured in the presence or absence of forskolin and 1,25-dihydroxyvitamin D3[ 1α,25-(OH)2D3]. Forskolin and 1α,25-(OH)2D3 induced the expression of 1α-hydroxylase and 24-hydroxylase, respectively, in a dose- and time-dependent manner. In the absence of stimulants, the expression of 1α-hydroxylase and 24-hydroxylase was detected from days 13.5–17.5 gestation. The expression of vitamin D receptor and megalin was detected from days 13.5 and 11.5, respectively. Next, signals for the expression of either 1α-hydroxylase or 24-hydroxylase were detected by whole mount in situ hybridization in kidney explants taken from embryo at 15.5 days gestation after the appropriate stimulation. However, the localization of signals differed between the two enzymes; 1α-hydroxylase messenger RNA was expressed in the inner area of the kidney explants, whereas 24-hydroxylase messenger RNA was expressed in the surface area. The expression of both hydroxylases was restricted to the epithelium of developing renal tubules. The pattern of megalin expression was similar to that of 1α-hydroxylase expression. To confirm the difference in distribution of 1α-hydroxylase and 24-hydroxylase transcripts, the explants were hybridized with probes for both 1α-hydroxylase and 24-hydroxylase using double labeling techniques after simultaneous stimulation with forskolin and 1α,25-(OH)2D3, resulting in the detection at different locations of positive signals for the two enzymes. These results suggest that the expression of 1α-hydroxylase is induced in a distinct epithelium of renal tubules from that of 24-hydroxylase even at the early stage of kidney development before glomerulogenesis.
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Novakovic, Boris, Mandy Sibson, Hong Kiat Ng, Ursula Manuelpillai, Vardhman Rakyan, Thomas Down, Stephan Beck, et al. "Placenta-specific Methylation of the Vitamin D 24-Hydroxylase Gene." Journal of Biological Chemistry 284, no. 22 (February 23, 2009): 14838–48. http://dx.doi.org/10.1074/jbc.m809542200.
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Latic, Nejla, and Reinhold G. Erben. "Interaction of Vitamin D with Peptide Hormones with Emphasis on Parathyroid Hormone, FGF23, and the Renin-Angiotensin-Aldosterone System." Nutrients 14, no. 23 (December 6, 2022): 5186. http://dx.doi.org/10.3390/nu14235186.
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The seminal discoveries that parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are major endocrine regulators of vitamin D metabolism led to a significant improvement in our understanding of the pivotal roles of peptide hormones and small proteohormones in the crosstalk between different organs, regulating vitamin D metabolism. The interaction of vitamin D, FGF23 and PTH in the kidney is essential for maintaining mineral homeostasis. The proteohormone FGF23 is mainly secreted from osteoblasts and osteoclasts in the bone. FGF23 acts on proximal renal tubules to decrease production of the active form of vitamin D (1,25(OH)2D) by downregulating transcription of 1α-hydroxylase (CYP27B1), and by activating transcription of the key enzyme responsible for vitamin D degradation, 24-hydroxylase (CYP24A1). Conversely, the peptide hormone PTH stimulates 1,25(OH)2D renal production by upregulating the expression of 1α-hydroxylase and downregulating that of 24-hydroxylase. The circulating concentration of 1,25(OH)2D is a positive regulator of FGF23 secretion in the bone, and a negative regulator of PTH secretion from the parathyroid gland, forming feedback loops between kidney and bone, and between kidney and parathyroid gland, respectively. In recent years, it has become clear that vitamin D signaling has important functions beyond mineral metabolism. Observation of seasonal variations in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in non-renal tissues such as cardiomyocytes, endothelial and smooth muscle cells, suggested that vitamin D may play a role in maintaining cardiovascular health. Indeed, observational studies in humans have found an association between vitamin D deficiency and hypertension, left ventricular hypertrophy and heart failure, and experimental studies provided strong evidence for a role of vitamin D signaling in the regulation of cardiovascular function. One of the proposed mechanisms of action of vitamin D is that it functions as a negative regulator of the renin-angiotensin-aldosterone system (RAAS). This finding established a novel link between vitamin D and RAAS that was unexplored until then. During recent years, major progress has been made towards a more complete understanding of the mechanisms by which FGF23, PTH, and RAAS regulate vitamin D metabolism, especially at the genomic level. However, there are still major gaps in our knowledge that need to be filled by future research. The purpose of this review is to highlight our current understanding of the molecular mechanisms underlying the interaction between vitamin D, FGF23, PTH, and RAAS, and to discuss the role of these mechanisms in physiology and pathophysiology.
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Wang, Yongji, Jinge Zhu, and Hector F. DeLuca. "The vitamin D receptor in the proximal renal tubule is a key regulator of serum 1α,25-dihydroxyvitamin D3." American Journal of Physiology-Endocrinology and Metabolism 308, no. 3 (February 1, 2015): E201—E205. http://dx.doi.org/10.1152/ajpendo.00422.2014.
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It is well established that the mitochondria of proximal convoluted tubule cells of the kidney are the site of production of circulating 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The production of 1,25(OH)2D3 at this site is tightly regulated. Parathyroid hormone markedly stimulates 1,25(OH)2D3 production, whereas 1,25(OH)2D3 itself suppresses production. The mechanism of suppression by 1,25(OH)2D3 has not yet been elucidated. We have now found that in the absence of vitamin D (vitamin D deficiency), the vitamin D receptor (VDR) is found in the interior of the apical brush border of the proximal tubule cells. This is unique for the proximal tubule cells, since this has not been observed in the distal tubule cells or in other epithelial cells, such as intestinal mucosa. Administration of 1,25(OH)2D3 to vitamin D-deficient rats results in the movement of VDR from the brush border to the cytoplasm and nucleus presumably bound to reabsorbed 1,25(OH)2D3. The VDR bound to 1,25(OH)2D3 suppresses expression of 25-hydroxyvitamin D3 1α-hydroxylase and stimulates the 25-hydroxyvitamin D3 24-hydroxylase. Thus, VDR in the apical brush border of the proximal convoluted tubule cells serves to “sense” the level of circulating 1,25(OH)2D3 and modulates the activity of the 1α-hydroxylase and the 24-hydroxylase accordingly.
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Mata-Greenwood, Eugenia, Hillary F. Huber, Cun Li, and Peter W. Nathanielsz. "Role of pregnancy and obesity on vitamin D status, transport, and metabolism in baboons." American Journal of Physiology-Endocrinology and Metabolism 316, no. 1 (January 1, 2019): E63—E72. http://dx.doi.org/10.1152/ajpendo.00208.2018.
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Human studies show that obesity is associated with vitamin D insufficiency, which contributes to obesity-related disorders. Our aim was to elucidate the regulation of vitamin D during pregnancy and obesity in a nonhuman primate species. We studied lean and obese nonpregnant and pregnant baboons. Plasma 25-hydroxy vitamin D (25-OH-D) and 1α,25-(OH)2-D metabolites were analyzed using ELISA. Vitamin D-related gene expression was studied in maternal kidney, liver, subcutaneous fat, and placental tissue using real-time PCR and immunoblotting. Pregnancy was associated with an increase in plasma bioactive vitamin D levels compared with nonpregnant baboons in both lean and obese groups. Pregnant baboons had lower renal 24-hydroxylase CYP24A1 protein and chromatin-bound vitamin D receptor (VDR) than nonpregnant baboons. In contrast, pregnancy upregulated the expression of CYP24A1 and VDR in subcutaneous adipose tissue. Obesity decreased vitamin D status in pregnant baboons (162 ± 17 vs. 235 ± 28 nM for 25-OH-D, 671 ± 12 vs. 710 ± 10 pM for 1α,25-(OH)2-D; obese vs. lean pregnant baboons, P < 0.05). Lower vitamin D status correlated with decreased maternal renal expression of the vitamin D transporter cubulin and the 1α-hydroxylase CYP27B1. Maternal obesity also induced placental downregulation of the transporter megalin (LRP2), CYP27B1, the 25-hydroxylase CYP2J2, and VDR. We conclude that baboons represent a novel species to evaluate vitamin D regulation. Both pregnancy and obesity altered vitamin D status. Obesity-induced downregulation of vitamin D transport and bioactivation genes are novel mechanisms of obesity-induced vitamin D regulation.
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Carbone, Federico, and Fabrizio Montecucco. "The Role of the Intraplaque Vitamin D System in Atherogenesis." Scientifica 2013 (2013): 1–14. http://dx.doi.org/10.1155/2013/620504.
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Vitamin D has been shown to play critical activities in several physiological pathways not involving the calcium/phosphorus homeostasis. The ubiquitous distribution of the vitamin D receptor that is expressed in a variety of human and mouse tissues has strongly supported research on these “nonclassical” activities of vitamin D. On the other hand, the recent discovery of the expression also for vitamin D-related enzymes (such as 25-hydroxyvitamin D-1α-hydroxylase and the catabolic enzyme 1,25-dihydroxyvitamin D-24-hydroxylase) in several tissues suggested that the vitamin D system is more complex than previously shown and it may act within tissues through autocrine and paracrine pathways. This updated model of vitamin D axis within peripheral tissues has been particularly investigated in atherosclerotic pathophysiology. This review aims at updating the role of the local vitamin D within atherosclerotic plaques, providing an overview of both intracellular mechanisms and cell-to-cell interactions. In addition, clinical findings about the potential causal relationship between vitamin D deficiency and atherogenesis will be analysed and discussed.
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Inoue, Yoshio, Hiroko Segawa, Ichiro Kaneko, Setsuko Yamanaka, Kenichiro Kusano, Eri Kawakami, Junya Furutani, et al. "Role of the vitamin D receptor in FGF23 action on phosphate metabolism." Biochemical Journal 390, no. 1 (August 9, 2005): 325–31. http://dx.doi.org/10.1042/bj20041799.
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FGF23 (fibroblast growth factor 23) is a novel phosphaturic factor that influences vitamin D metabolism and renal re-absorption of Pi. The goal of the present study was to characterize the role of the VDR (vitamin D receptor) in FGF23 action using VDR(−/−) (VDR null) mice. Injection of FGF23M (naked DNA encoding the R179Q mutant of human FGF23) into VDR(−/−) and wildtype VDR(+/+) mice resulted in an elevation in serum FGF23 levels, but had no effect on serum calcium or parathyroid hormone levels. In contrast, injection of FGF23M resulted in significant decreases in serum Pi levels, renal Na/Pi co-transport activity and type II transporter protein levels in both groups when compared with controls injected with mock vector or with FGFWT (naked DNA encoding wild-type human FGF23). Injection of FGF23M resulted in a decrease in 25-hydroxyvitamin D 1α-hydroxylase mRNA levels in VDR(−/−) and VDR(+/+) mice, while 25-hydroxyvitamin D 24-hydroxylase mRNA levels were significantly increased in FGF23M-treated animals compared with mock vector control- or FGF23WT-treated animals. The degree of 24-hydroxylase induction by FGF23M was dependent on the VDR, since FGF23M significantly reduced the levels of serum 1,25(OH)2D3 [1,25-hydroxyvitamin D3] in VDR(+/+) mice, but not in VDR(−/−) mice. We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1α-hydroxylase levels by a mechanism that is independent of the VDR. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1,25(OH)2D3 levels induced by FGF23 are dependent on the VDR.
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Tebben, Peter J., Ravinder J. Singh, and Rajiv Kumar. "Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment." Endocrine Reviews 37, no. 5 (September 2, 2016): 521–47. http://dx.doi.org/10.1210/er.2016-1070.
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AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.
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St-Arnaud, René, Alice Arabian, Rose Travers, Frank Barletta, Mihali Raval-Pandya, Kelli Chapin, Jos Depovere, et al. "Deficient Mineralization of Intramembranous Bone in Vitamin D-24-Hydroxylase-Ablated Mice Is Due to Elevated 1,25-Dihydroxyvitamin D and Not to the Absence of 24,25-Dihydroxyvitamin D*." Endocrinology 141, no. 7 (July 1, 2000): 2658–66. http://dx.doi.org/10.1210/endo.141.7.7579.
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The 25-hydroxyvitamin D-24-hydroxylase enzyme (24-OHase) is responsible for the catabolic breakdown of 1,25-dihydroxyvitamin D[ 1,25(OH)2D], the active form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvitamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear. We report that mice with a targeted inactivating mutation of the 24-OHase gene had impaired 1,25(OH)2D catabolism. Surprisingly, complete absence of 24-OHase activity during development leads to impaired intramembranous bone mineralization. This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a targeted mutation in the vitamin D receptor gene, confirming that the elevated 1,25(OH)2D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid. Our results confirm the physiological importance of the 24-OHase enzyme for maintaining vitamin D homeostasis, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolite during bone development.
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Jovičić, Snežana, Svetlana Ignjatović, and Nada Majkić-Singh. "Biochemistry and metabolism of vitamin D / Biohemija i metabolizam vitamina D." Journal of Medical Biochemistry 31, no. 4 (October 1, 2012): 309–15. http://dx.doi.org/10.2478/v10011-012-0028-8.
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Summary Vitamin D is not technically a vitamin, since it is not an essential dietary factor. It is rather a prohormone produced photochemically in the skin from 7-dehydrocholesterol. Vitamin D and its metabolites may be categorized as either cholecalciferols or ergocalciferols. Cholecalciferol (vi - tamin D3) is the parent compound of the naturally occurring family and is produced in the skin from 7-dehydrocholesterol on exposure to the ultraviolet B portion of sunlight. Vitamin D2 (ergocalciferol), the parent compound of the other family, is manufactured by irradiation of ergosterol produced by yeasts and its potency is less than one-third of vitamin D3’s potency. The steps in the vitamin D endocrine system include the following: 1) the photoconversion of 7- dehydrocholesterol to vitamin D3 in the skin or dietary intake of vitamin D3; 2) metabolism of vitamin D3 by the liver to 25-hydroxyvitamin-D3 [25(OH)D3 ], the major form of vitamin D circulating in the blood compartment; 3) conversion of 25(OH)D3 by the kidney (functioning as an endocrine gland) to the hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 ]; 4) systemic transport of the dihydroxylated metabolite 1,25(OH)2D3 to distal target organs; and 5) binding of 1,25(OH)2D3 to a nuclear receptor (VDR) at target organs, followed by generation of appropriate biological responses. The activation of vitamin D to its hormonal form is mediated by cytochrome P450 enzymes. Six cytochrome P450 (CYP) isoforms have been shown to hydroxylate vitamin D. Four of these, CYP27A1, CYP2R1, CYP3A4 and CYP2J3, are candidates for the enzyme vitamin D 25-hy - droxylase that is involved in the first step of activation. The highly regulated, renal enzyme 25-hydroxyvitamin D-1a-hy - dro xylase contains the component CYP27B1, which completes the activation pathway to the hormonal form 1,25(OH)2D3. A five-step inactivation pathway from 1,25(OH)2D3 to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally in du - ced in vitamin D target cells by the action of 1,25(OH)2D3. An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein (DBP), which carries vitamin D3 and its metabolites to their metabolism and target organs. DBP is a specific, high-affinity transport protein. It is synthesized by the liver and circulates in great excess, with fewer than 5% of the binding sites normally occupied. 1,25(OH)2D3, acts as a ligand for a nuclear transcription factor, vitamin D receptor - VDR, which like all other nuclear receptors, regulates gene transcription and cell function. The widespread presence of VDR, and the key activating (1a-hydroxylase, CYP27B1) and inactivating (24-hydroxylase, CYP24A1) en - zy mes in most mammalian cells means that the cells in these tissues have the potential to produce biological res pon ses, depending on the availability of appropriate amounts of vi - tamin D3. Thanks to this widespread presence of elements of vitamin D endocrine system, its biological features are being recognized outside bone tissue, i.e. calcium and pho - sphate metabolism.
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Kasuga, Hisao, Naobumi Hosogane, Kunio Matsuoka, Ikuo Mori, Yasufumi Sakura, Kozo Shimakawa, Toshimasa Shinki, Tatsuo Suda, and Shigehisa Taketomi. "Characterization of transgenic rats constitutively expressing vitamin D-24-hydroxylase gene." Biochemical and Biophysical Research Communications 297, no. 5 (October 2002): 1332–38. http://dx.doi.org/10.1016/s0006-291x(02)02254-4.
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Luo, Wei, Pamela A. Hershberger, Donald L. Trump, and Candace S. Johnson. "24-Hydroxylase in cancer: Impact on vitamin D-based anticancer therapeutics." Journal of Steroid Biochemistry and Molecular Biology 136 (July 2013): 252–57. http://dx.doi.org/10.1016/j.jsbmb.2012.09.031.
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Song, Yurong, and James C. Fleet. "Intestinal Resistance to 1,25 Dihydroxyvitamin D in Mice Heterozygous for the Vitamin D Receptor Knockout Allele." Endocrinology 148, no. 3 (March 1, 2007): 1396–402. http://dx.doi.org/10.1210/en.2006-1109.
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We tested the hypothesis that low vitamin D receptor (VDR) level causes intestinal vitamin D resistance and intestinal calcium (Ca) malabsorption. To do so, we examined vitamin D regulated duodenal Ca absorption and gene expression [transient receptor potential channel, vallinoid subfamily member 6 (TRPV6), 24-hydroxylase, calbindin D9k (CaBP) mRNA, and CaBP protein] in wild-type mice and mice with reduced tissue VDR levels [i.e. heterozygotes for the VDR gene knockout (HT)]. Induction of 24-hydroxylase mRNA levels by 1,25 dihydroxyvitamin D3 [1,25(OH)2 D3] injection was significantly reduced in the duodenum and kidney of HT mice in both time-course and dose-response experiments. TRPV6 and CaBP mRNA levels in duodenum were significantly induced after 1,25(OH)2 D3 injection, but there was no difference in response between wild-type and HT mice. Feeding a low-calcium diet for 1 wk increased plasma PTH, renal 1α-hydroxylase (CYP27B1) mRNA level, and plasma 1,25(OH)2 D3, and this response was greater in HT mice (by 88, 55, and 37% higher, respectively). In contrast, duodenal TRPV6 and CaBP mRNA were not higher in HT mice fed the low-calcium diet. However, the response of duodenal Ca absorption and CaBP protein to increasing 1,25(OH)2 D3 levels was blunted by 40% in HT mice. Our data show that low VDR levels lead to resistance of intestinal Ca absorption to 1,25(OH)2 D3, and this resistance may be due to a role for the VDR (and VDR level) in the translation of CaBP.
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Xie, Zhongjian, Sandra Chang, Yuko Oda, and Daniel D. Bikle. "Hairless Suppresses Vitamin D Receptor Transactivation in Human Keratinocytes." Endocrinology 147, no. 1 (January 1, 2006): 314–23. http://dx.doi.org/10.1210/en.2005-1111.
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The vitamin D receptor (VDR) and its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are required for normal keratinocyte differentiation. Both the epidermis and the hair follicle are disrupted in VDR-null mice. Hairless (Hr), a presumptive transcription factor with no known ligand, when mutated, disrupts hair follicle cycling similar to the effects of VDR mutations. Hr, like VDR, is found in the nuclei of keratinocytes in both epidermis and hair follicle. To investigate the potential interaction between Hr and VDR on keratinocyte differentiation, we examined the effect of Hr expression on vitamin D-responsive genes in normal human keratinocytes. Inhibition of Hr expression in keratinocytes potentiated the induction of vitamin D-responsive genes, including involucrin, transglutaminase, phospholipase C-γ1, and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by 1,25(OH)2D3. Overexpression of Hr in human keratinocytes suppressed the induction of these vitamin D-responsive genes by 1,25(OH)2D3. Coimmunoprecipitation, DNA mobility shift assays, and chromatin immunoprecipitation revealed that Hr binds to VDR in human keratinocytes. Hr binding to the VDR was eliminated by 1,25(OH)2D3, which recruited the coactivator vitamin D receptor-interacting protein 205 (DRIP205) to the VDR/vitamin D response element complex. These data indicate that Hr functions as a corepressor of VDR to block 1,25(OH)2D3 action on keratinocytes.
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Vidal, Marcos, Chilakamarti V. Ramana, and Adriana S. Dusso. "Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription." Molecular and Cellular Biology 22, no. 8 (April 15, 2002): 2777–87. http://dx.doi.org/10.1128/mcb.22.8.2777-2787.2002.
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ABSTRACT The cytokine gamma interferon (IFN-γ) and the calcitropic steroid hormone 1,25-dihydroxyvitamin D (1,25D) are activators of macrophage immune function. In sarcoidosis, tuberculosis, and several granulomatoses, IFN-γ induces 1,25D synthesis by macrophages and inhibits 1,25D induction of 24-hydroxylase, a key enzyme in 1,25D inactivation, causing high levels of 1,25D in serum and hypercalcemia. This study delineates IFN-γ-1,25D cross talk in human monocytes-macrophages. Nuclear accumulation of Stat1 and vitamin D receptor (VDR) by IFN-γ and 1,25D promotes protein-protein interactions between Stat1 and the DNA binding domain of the VDR. This prevents VDR-retinoid X receptor (RXR) binding to the vitamin D-responsive element, thus diverting the VDR from its normal genomic target on the 24-hydroxylase promoter and antagonizing 1,25D-VDR transactivation of this gene. In contrast, 1,25D enhances IFN-γ action. Stat1-VDR interactions, by preventing Stat1 deactivation by tyrosine dephosphorylation, cooperate with IFN-γ/Stat1-induced transcription. This novel 1,25D-IFN-γ cross talk explains the pathogenesis of abnormal 1,25D homeostasis in granulomatous processes and provides new insights into 1,25D immunomodulatory properties.
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Ma, Rong, Yang Gu, Shuang Zhao, Jingxia Sun, Lynn J. Groome, and Yuping Wang. "Expressions of vitamin D metabolic components VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR in placentas from normal and preeclamptic pregnancies." American Journal of Physiology-Endocrinology and Metabolism 303, no. 7 (October 1, 2012): E928—E935. http://dx.doi.org/10.1152/ajpendo.00279.2012.
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Vitamin D insufficiency/deficiency during pregnancy has been linked to increased risk of preeclampsia. Placenta dysfunction plays an important role in the pathogenesis of this pregnancy disorder. In this study, we tested the hypothesis that disturbed vitamin D metabolism takes place in preeclamptic placentas. Protein expressions of vitamin D binding protein (VDBP), 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), 24-hydroxylase (CYP24A1), and vitamin D receptor (VDR) were examined in placentas from normotensive and preeclamptic pregnancies. By immunostaining we found that in normal placenta VDBP, CYP24A1, and VDR expressions are localized mainly in trophoblasts, whereas CYP2R1 and CYP27B1 expressions are localized mainly in villous core fetal vessel endothelium. Protein expressions of CYP2R1 and VDR are reduced, but CYP27B1 and CYP24A1 expressions are elevated, in preeclamptic compared with normotensive placentas. Because increased oxidative stress is an underlying pathophysiology in placental trophoblasts in preeclampsia, we further determined whether oxidative stress contributes to altered vitamin D metabolic system in placental trophoblasts. Trophoblasts isolated from normal-term placentas were treated with hypoxic-inducing agent CoCl2, and protein expressions of VDBP, CYP2R1, CYP27B1, CYP24A1, and VDR were determined. We found that hypoxia-induced downregulation of VDBP, CYP2R1, and VDR and upregulation of CYP27B1 and CYP24A1 expressions were consistent with that seen in preeclamptic placentas. CuZnSOD expression was also downregulated in trophoblasts treated with CoCl2. These results provide direct evidence of disrupted vitamin D metabolic homeostasis in the preeclamptic placenta and suggest that increased oxidative stress could be a causative factor of altered vitamin D metabolism in preeclamptic placentas.
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Penna-Martinez, Marissa, Gesine Meyer, Anette Boe Wolff, Beate Skinningsrud, Corrado Betterle, Alberto Falorni, William Ollier, et al. "Vitamin D status and pathway genes in five European autoimmune Addison’s disease cohorts." European Journal of Endocrinology 184, no. 3 (March 2021): 377–85. http://dx.doi.org/10.1530/eje-20-0956.
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Objective While vitamin D regulates immune cells, little is known about it in autoimmune Addison’s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes. Design Cross-sectional study. Methods A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). Results Vitamin D deficiency (25(OH)D3 10–20 ng/mL) was highly prevalent in AAD patients (34–57%), 5–22% were severely deficient (<10 ng/mL), 28–38% insufficient (20–30 ng/mL) and only 7–14% sufficient (>30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (P = 0.03/0.003 and P = 1 × 10-5/< 1 × 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/mL) and synthesize less 1,25(OH)2D3. Conclusion Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.
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Wu, S., J. Finch, M. Zhong, E. Slatopolsky, M. Grieff, and A. J. Brown. "Expression of the renal 25-hydroxyvitamin D-24-hydroxylase gene: regulation by dietary phosphate." American Journal of Physiology-Renal Physiology 271, no. 1 (July 1, 1996): F203—F208. http://dx.doi.org/10.1152/ajprenal.1996.271.1.f203.
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1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] plays a key role in phosphate (Pi) homeostasis through its phosphatemic actions on intestine and bone. In turn, dietary Pi restriction increases serum 1,25(OH)2D3 by stimulating its production, but its effect on vitamin D catabolism is less clear. Here we have examined the effects of dietary Pi on the expression of the renal vitamin D-24-hydroxylase (24-OHase), the first enzyme in the catabolic pathway for vitamin D compounds. Rats fed a low Pi (0.02% P) diet showed a fivefold decrease in renal 24-OHase mRNA compared with rats fed a normal Pi (0.67% P) diet. 24-OHase mRNA and 24-OHase activity decreased within 24 h of Pi restriction, reached a minimum by 48 h, and remained low through 14 days. Decreased 24-OHase mRNA was observed with more moderate Pi restriction (0.2% P), but higher Pi (1.2% P) did not increase 24-OHase mRNA over the 0.8% P diet. 24-OHase mRNA correlated well with plasma Pi (r = 0.862, P < 0.001). In conclusion, renal 24-OHase expression is regulated by dietary phosphate at the mRNA level.
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Luo, Wei, Adam R. Karpf, Kristin K. Deeb, Josephia R. Muindi, Carl D. Morrison, Candace S. Johnson, and Donald L. Trump. "Epigenetic Regulation of Vitamin D 24-Hydroxylase/CYP24A1 in Human Prostate Cancer." Cancer Research 70, no. 14 (June 29, 2010): 5953–62. http://dx.doi.org/10.1158/0008-5472.can-10-0617.
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Shimada, Takashi, Yuji Yamazaki, Motoo Takahashi, Hisashi Hasegawa, Itaru Urakawa, Takeshi Oshima, Kaori Ono, et al. "Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism." American Journal of Physiology-Renal Physiology 289, no. 5 (November 2005): F1088—F1095. http://dx.doi.org/10.1152/ajprenal.00474.2004.
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FGF23 suppresses both serum phosphate and 1,25-dihydroxyvitamin D [1,25D] levels in vivo. Because 1,25D itself is a potent regulator of phosphate metabolism, it has remained unclear whether FGF23-induced changes in phosphate metabolism were caused by a 1,25D-independent mechanism. To address this issue, we intravenously administered recombinant FGF23 to vitamin D receptor (VDR) null (KO) mice as a rapid bolus injection and evaluated the early effects of FGF23. Administration of recombinant FGF23 further decreased the serum phosphate level in VDR KO mice, accompanied by a reduction in renal sodium-phosphate cotransporter type IIa (NaPi2a) protein abundance and a reduced renal 25-hydroxyvitamin D-1α-hydroxylase (1αOHase) mRNA level. Thus FGF23-induced changes in NaPi2a and 1αOHase expression are independent of the 1,25D/VDR system. However, 24-hydroxylase (24OHase) mRNA expression remained undetectable by the treatment with FGF23. We also analyzed the regulatory mechanism for FGF23 expression. The serum FGF23 level was almost undetectable in VDR KO mice, whereas dietary calcium supplementation significantly increased circulatory levels of FGF23 and its mRNA abundance in bone. This finding indicates that calcium is another determinant of FGF23 production that occurs independently of the VDR-mediated mechanism. In contrast, dietary phosphate supplementation failed to induce FGF23 expression in the absence of VDR, whereas marked elevation in circulatory FGF23 was observed in wild-type mice fed with a high-phosphate diet. Taken together, FGF23 works, at least in part, in a VDR-independent manner, and FGF23 production is also regulated by multiple mechanisms involving VDR-independent pathways.
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Scott, P., D. Ouimet, Y. Proulx, M. L. Trouvé, G. Guay, B. Gagnon, L. Valiquette, and A. Bonnardeaux. "The 1 alpha-hydroxylase locus is not linked to calcium stone formation or calciuric phenotypes in French-Canadian families." Journal of the American Society of Nephrology 9, no. 3 (March 1998): 425–32. http://dx.doi.org/10.1681/asn.v93425.
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Calcium urolithiasis is often associated with increased intestinal absorption and urine excretion of calcium, and has been suggested to result from increased vitamin D production. The role of the enzyme 1 alpha-hydroxylase, the rate-limiting step in active vitamin D production, was evaluated in 36 families, including 28 sibships with at least a pair of affected sibs, using qualitative and quantitative trait linkage analyses. Sibs with a verified calcium urolithiasis passage (n = 117) had higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)2 vitamin D levels (P = 0.02) compared with nonstone-forming sibs (n = 120). Markers from a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 12q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (146 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (> or = 3 episodes) stone-forming sibs. Two-point and multipoint analyses did not reveal excess in alleles shared among affected sibs at the VDD1 locus. Linkage of stone formation to the VDD1 locus could be excluded, respectively, with a lambda d of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed no evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)2 vitamin D levels, and Ca/cr ratios. This study shows absence of linkage of the putative 1 alpha-hydroxylase locus to calcium stone formation or to quantitative traits associated with idiopathic hypercalciuria. In addition, there is coaggregation of calciuric and oxaluric phenotypes with stone formation.
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Armbrecht, H. J., M. L. Chen, T. L. Hodam, and M. A. Boltz. "Induction of 24-hydroxylase cytochrome P450 mRNA by 1,25-dihydroxyvitamin D and phorbol esters in normal rat kidney (NRK-52E) cells." Journal of Endocrinology 153, no. 2 (May 1997): 199–205. http://dx.doi.org/10.1677/joe.0.1530199.
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Abstract The biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D), acts on intestinal, renal, and bone cells to regulate skeletal and mineral metabolism. 1,25(OH)2D also induces 24-hydroxylase activity in these target cells. The 24-hydroxylase hydroxylates 1,25(OH)2D to 1,24,25-trihydroxyvitamin D and 25(OH)D to 24,25-dihydroxyvitamin D. The production of 1,24,25-trihydroxyvitamin D is thought to be the first step in the inactivation of 1,25(OH)2D by its target tissues. Previous studies have characterized the induction of the 24-hydroxylase by 1,25(OH)2D in clonal cell lines from intestine and bone. The purpose of these studies was to characterize the induction of the 24-hydroxylase by 1,25(OH)2D in the kidney, using the clonal rat renal cell line NRK-52E. 1,25(OH)2D (10−7 m) increased the mRNA levels for the cytochrome P450 component of the 24-hydroxylase (P450cc24) by sevenfold after 36 h in NRK-52E cells. 1,25(OH)2D increased P450cc24 mRNA levels in a dose-dependent manner with an EC50 of 10−8 m. In parallel experiments, 1,25(OH)2D significantly increased 24-hydroxylase enzyme activity after 48–72 h. The increase in P450cc24 mRNA induced by 1,25(OH)2D required on-going transcription and translation and was inhibited by H-7, a protein kinase C inhibitor. Tetradecanoyl phorbol acetate markedly increased the magnitude of the tissue responsiveness to 1,25(OH)2D by a protein kinase C-dependent pathway. These studies demonstrate that 1,25(OH)2D increases P450cc24 mRNA levels in NRK-52E cells by a mechanism requiring new protein synthesis and involving protein kinase C. This is in contrast to the action of 1,25(OH)2D in intestinal cells, which does not require new protein synthesis, and in osteoblastic cells, which does not involve protein kinase C. Journal of Endocrinology (1997) 153, 199–205
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Zierold, Claudia, Hisham M. Darwish, and Hector F. DeLuca. "Two Vitamin D Response Elements Function in the Rat 1,25-Dihydroxyvitamin D 24-Hydroxylase Promoter." Journal of Biological Chemistry 270, no. 4 (January 27, 1995): 1675–78. http://dx.doi.org/10.1074/jbc.270.4.1675.
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Bolt, Merry J. G., Sally A. Holick, Michael F. Holick, Julia MacLaughlin, and Irwin H. Rosenberg. "24-Dehydrovitamin D is a potent inhibitor of rat liver microsomal vitamin D-25-hydroxylase." Archives of Biochemistry and Biophysics 266, no. 2 (November 1988): 532–38. http://dx.doi.org/10.1016/0003-9861(88)90286-x.
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Jones, Glenville, David E. Prosser, and Martin Kaufmann. "25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): Its important role in the degradation of vitamin D." Archives of Biochemistry and Biophysics 523, no. 1 (July 2012): 9–18. http://dx.doi.org/10.1016/j.abb.2011.11.003.
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Pitcher, T., I. N. Sergeev, and R. Buffenstein. "Vitamin D metabolism in the Damara mole-rat is altered by exposure to sunlight yet mineral metabolism is unaffected." Journal of Endocrinology 143, no. 2 (November 1994): 367–74. http://dx.doi.org/10.1677/joe.0.1430367.
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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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Demers, C., J. Lemay, G. N. Hendy, and M. Gascon-Barré. "Comparative in vivo expression of the calcitriol-24-hydroxylase gene in kidney and intestine." Journal of Molecular Endocrinology 18, no. 1 (February 1997): 37–48. http://dx.doi.org/10.1677/jme.0.0180037.
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ABSTRACT Although the kidney and intestine are among the major organs involved in both the biotransformation and action of vitamin D3, they exhibit very distinct roles in calcium and D3 homeostasis. The aim of the present studies was to investigate the relative in vivo responsiveness of renal and intestinal 1,25(OH)2D3-24-hydroxylase (24-hydroxylase) mRNA levels to calcitriol (1,25(OH)2D3) following acute or chronic 1,25(OH)2D3 exposure using hypocalcemic vitamin D-depleted rats as an experimental model. Intestinal 24-hydroxylase mRNA levels were very responsive to a single i.v. injection of 2·4, 12 or 120nmol 1,25(OH)2D3/kg but in kidney the mRNA levels only increased following exposure to the highest 1,25(OH)2D3 concentration, and exhibited a maximum response only 30% of that in the intestine despite similar tissue uptake of the hormone. To evaluate whether the kidney might preferentially respond to endogenously produced 1,25(OH)2D3, animals received increasing doses of 25(OH)D3. Although the intestinal 24-hydroxylase transcript was highly induced, the renal transcript was unresponsive to 25(OH)D3 treatment despite circulating 1,25(OH)2D3 concentrations of 24 nmol/l. By contrast, intestinal 24-hydroxylase mRNA levels were largely unresponsive to long-term calcitriol administration while the renal transcript, although insensitive to a physiological dose, responded to pharmacological 1,25(OH)2D3 doses. However, when challenged acutely with 1,25(OH)2D3 following chronic exposure, the kidney 24-hydroxylase mRNA levels remained largely unresponsive in contrast to the intestinal transcript which was markedly induced. These data indicate that significant differences exist in the in vivo tissue responsiveness of the 24-hydroxylase mRNA. Indeed, the gene exhibited high intestinal responsiveness to acutely, but not chronically, administered 1,25(OH)2D3, while in the kidney it only responded to high exogenous 1,25(OH)2D3 delivered either acutely or chronically. In addition, these site-specific regulatory mechanisms governing the expression of the 24-hydroxylase gene are independent of the endocrine calcium status and render the kidney relatively resistant to endogenously produced 1,25(OH)2D3.
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Lim, Kenneth, Guerman Molostvov, Maria Lubczanska, Simon Fletcher, Rosemary Bland, Thomas F. Hiemstra, and Daniel Zehnder. "Impaired arterial vitamin D signaling occurs in the development of vascular calcification." PLOS ONE 15, no. 11 (November 19, 2020): e0241976. http://dx.doi.org/10.1371/journal.pone.0241976.
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Conflicting data exists as to whether vitamin D receptor agonists (VDRa) are protective of arterial calcification. Confounding this, is the inherent physiological differences between human and animal experimental models and our current fragmented understanding of arterial vitamin D metabolism, their alterations in disease states and responses to VDRa’s. Herein, the study aims to address these problems by leveraging frontiers in human arterial organ culture models. Human arteries were collected from a total of 24 patients (healthy controls, n = 12; end-stage CKD, n = 12). Cross-sectional and interventional studies were performed using arterial organ cultures treated with normal and calcifying (containing 5mmol/L CaCl2 and 5mmol/L β-glycerophosphate) medium, ex vivo. To assess the role of VDRa therapy, arteries were treated with either calcitriol or paricalcitol. We found that human arteries express a functionally active vitamin D system, including the VDR, 1α-hydroxylase and 24-hydroxylase (24-OHase) components and these were dysregulated in CKD arteries. VDRa therapy increased VDR expression in healthy arteries (p<0.01) but not in CKD arteries. Arterial 1α-OHase (p<0.05) and 24-OHase mRNA and protein expression were modulated differentially in healthy and CKD arteries by VDRa therapy. VDRa exposure suppressed Runx2 and MMP-9 expression in CKD arteries, however only paricalcitol suppressed MMP-2. VDRa exposure did not modulate arterial calcification in all organ culture models. However, VDRa reduced expression of senescence associated β-galactosidase (SAβG) staining in human aortic-smooth muscle cells under calcifying conditions, in vitro. In conclusion, maladaptation of arterial vitamin D signaling components occurs in CKD. VDRa exposure can exert vasculo-protective effects and seems critical for the regulation of arterial health in CKD.
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Li, S. M., L. H. Ouyang, and D. G. Zhou. "Effects of vitamin D3 on expression of defensins, Toll-like receptors, and vitamin D receptor in liver, kidney, and spleen of Silky Fowl." Czech Journal of Animal Science 58, No. 1 (January 8, 2013): 1–7. http://dx.doi.org/10.17221/6519-cjas.
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The expression of avian β-defensins (AvBDs), Toll-like receptors (TLRs), and vitamin D receptor (VDR) following in vivo vitamin D<sub>3 </sub>injection was studied. Healthy 90-day Silky Fowls were abdominally injected with vitamin D<sub>3</sub> or untreated. Real-time PCR analyses revealed that injection of vitamin D<sub>3</sub> significantly (P < 0.05) up-regulated the expression of TLRs (TLR2, TLR5), VDR, AvBDs (AVBD-6, GAL-1), and 24-hydroxylase (CYP24A1) in the tissues (liver, spleen, and kidney) at various times 8–24 h post injection. These results suggest that expression of VDR, AvBDs, and TLRs seems to be induced by vitamin D<sub>3 </sub>and it was concluded that the tissues expressing TLRs and VDR respond to vitamin D<sub>3</sub> and in turn upregulate these tissues cellular functions to synthesize AvBDs. Intraperitoneal injection of vitamin D<sub>3</sub> likely resulted in enhancing the expression of AvBDs, TLRs, and VDR, which providedinsight into factors important for the control of the innateimmune response in the chickens.
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McMahon, Laura, Kyell Schwartz, Ozlem Yilmaz, Eleith Brown, Lisa K. Ryan, and Gill Diamond. "Vitamin D-Mediated Induction of Innate Immunity in Gingival Epithelial Cells." Infection and Immunity 79, no. 6 (March 21, 2011): 2250–56. http://dx.doi.org/10.1128/iai.00099-11.
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ABSTRACTHuman gingival epithelial cells (GEC) produce peptides, such as β-defensins and the cathelicidin LL-37, that are both antimicrobial and that modulate the innate immune response. In myeloid and airway epithelial cells, the active form of vitamin D3[1,25(OH)2D3] increases the expression and antibacterial activity of LL-37. To examine the activity of vitamin D on the innate immune defense of the gingival epithelium, cultured epithelial cells were treated with either 10−8M 1,25(OH)2D3or ethanol for up to 24 h. A time-dependent induction of LL-37 mRNA up to 13-fold at 24 h in both standard monolayer and three-dimensional cultures was observed. Induction of the vitamin D receptor and the 1-α-hydroxylase genes was also observed. The hydroxylase was functional, as LL-37 induction was observed in response to stimulation by 25(OH)D3. Through microarray analysis of other innate immune genes, CD14 expression increased 4-fold, and triggering receptor expressed on myeloid cells-1 (TREM-1) was upregulated 16-fold after 24 h of treatment with 1,25(OH)2D3. TREM-1 is a pivotal amplifier of the innate immune response in macrophages, leading to increased production by inflammatory response genes. Activation of TREM-1 on the GEC led to an increase in interleukin-8 (IL-8) mRNA levels. Incubation of three-dimensional cultures with 1,25(OH)2D3led to an increase in antibacterial activity against the periodontal pathogenAggregatibacter actinomycetemcomitanswhen the bacteria were added to the apical surface. This study is the first to demonstrate the effect of vitamin D on antibacterial defense of oral epithelial cells, suggesting that vitamin D3could be utilized to enhance the innate immune defense in the oral cavity.
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Mandel, M. L., B. Moorthy, and J. G. Ghazarian. "Reciprocal post-translational regulation of renal 1α- and 24-hydroxylases of 25-hydroxyvitamin D3 by phosphorylation of ferredoxin. mRNA-directed cell-free synthesis and immunoisolation of ferredoxin." Biochemical Journal 266, no. 2 (March 1, 1990): 385–92. http://dx.doi.org/10.1042/bj2660385.
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We have used a cell-free rabbit reticulocyte translational system programmed with polyadenylated [poly(A)+] RNA prepared from chick kidney tissue to study the synthesis of nascent ferredoxin, a class of iron-sulphur-containing proteins functional in the renal mitochondrial 1 alpha- and 24-hydroxylases of 25-hydroxyvitamin D3. The synthesis of ferredoxin was monitored by determining [35S]methionine incorporation into ferredoxin and quantified by SDS/PAGE and autoradiography after immunoprecipitation from the total translation products. Compared with normal controls, vitamin D deprivation caused a significant increase in the net synthesis of nascent ferredoxin with an Mr of 12,000-13,000. [3H]Orotate incorporation as uridine into kidney poly(A)+ RNA was stimulated by aminophylline, a potent inducer of 25-hydroxyvitamin D3 24-hydroxylase; however, the amount of nascent ferredoxin synthesis was the same as in normal controls. Also, partially purified chick kidney mitochondrial cyclic AMP-stimulated protein kinase catalysed the phosphorylation of ferredoxin in vitro. The catalytic activity of the ferredoxin in 1 alpha- and 24-hydroxylations of 25-hydroxyvitamin D3 in reconstituted systems consisting of cytochrome P-450 and ferredoxin reductase was altered with ferredoxin phosphorylation. The phosphorylation caused inhibition of the 1 alpha-hydroxylase activity while at the same time it stimulated the 24-hydroxylase. Authentic 1 alpha,25- and 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 were used as standards to monitor the separation of the enzymic products by h.p.l.c. using methanol/water (4:1, v/v) as solvent. These results indicate that, in the absence of vitamin D or its metabolites in the deficient state, the synthesis of ferredoxin necessary for the 1 alpha-hydroxylase is accentuated, whereas the stimulation of the 24-hydroxylase requires the phosphorylation of existing ferredoxin without a net gain in its synthesis. This would suggest a post-translational regulation of the 1 alpha- and 24-hydroxylases. A model delineating the various aspects of this study is presented.
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Itoh, Susumu, Takuya Yoshimura, Osamu Iemura, Eitaro Yamada, Kazutake Tsujikawa, Yasuhiro Kohama, and Tsutomu Mimura. "Molecular cloning of 25-hydroxyvitamin D-3 24-hydroxylase (Cyp-24) from mouse kidney: its inducibility by vitamin D-3." Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1264, no. 1 (October 1995): 26–28. http://dx.doi.org/10.1016/0167-4781(95)00147-9.
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Walker, A. T., A. F. Stewart, E. A. Korn, T. Shiratori, M. A. Mitnick, and T. O. Carpenter. "Effect of parathyroid hormone-like peptides on 25-hydroxyvitamin D-1 alpha-hydroxylase activity in rodents." American Journal of Physiology-Endocrinology and Metabolism 258, no. 2 (February 1, 1990): E297—E303. http://dx.doi.org/10.1152/ajpendo.1990.258.2.e297.
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The role of vitamin D metabolism in the humoral hypercalcemia of malignancy syndrome (HHM) is unclear. We studied in vivo and in vitro effects of synthetic parathyroid hormone-like peptides (PTH-LPs) on rodent renal 25-OHD-1 alpha-hydroxylase activity. Infusion of mice with PTH-LP-(1-36) at 10 pmol/h for 12 and 24 h showed significant (429 +/- 139% and 937 +/- 413%, respectively) stimulation of control enzyme activity. Infusion for 36 h demonstrated diminution of activity to levels nearer to the unstimulated state (228 +/- 36% of control). In that maximal activity was observed after 24 h of infusion, we examined 1 alpha-hydroxylase activity after variable dosages of PTH-LP-(1-36) at this time point. Animals infused with PTH-LP-(1-36) at dosages of 2.5, 10, and 30 pmol/h for 24 h demonstrated 1 alpha-hydroxylase activities of 0.71 +/- 0.12, 4.74 +/- 2.09, and 9.91 +/- 1.01 ng.mg protein-1.20 min-1 (means +/- SD), respectively, all significantly greater than control activity (0.51 +/- 0.20 ng.mg protein-1.20 min-1). PTH-LP-(1-36) and PTH-LP-(1-74) were comparable in potency to bovine (b)PTH-(1-34) in stimulating 1 alpha-hydroxylase. Direct in vitro incubation of PTH-LP-(1-36) with renal slices resulted in stimulation of 1 alpha-hydroxylase activity up to 200% of control levels, comparable to that seen with equimolar concentrations of bPTH-(1-34).(ABSTRACT TRUNCATED AT 250 WORDS)
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Nygaard, Rie H., Marlene C. Nielsen, Kristian W. Antonsen, Carsten S. Højskov, Boe S. Sørensen, and Holger J. Møller. "Metabolism of 25-Hydroxy-Vitamin D in Human Macrophages Is Highly Dependent on Macrophage Polarization." International Journal of Molecular Sciences 23, no. 18 (September 19, 2022): 10943. http://dx.doi.org/10.3390/ijms231810943.
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Macrophages synthesize active vitamin D (1,25-dihydroxy-vitamin D) and express the vitamin D receptor in the nucleus; however, vitamin D metabolism in relation to macrophage polarization and function is not well understood. We studied monocyte-derived macrophages (MDMs) from human buffy coats polarized into M0, M1 (LPS + IFNγ), M2a (IL4 + IL13) and M2c (IL10) macrophage subtypes stimulated with 25-hydroxy-vitamin D (1000 and 10,000 nanomolar). We measured vitamin D metabolites (25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, 24,25-dihydroxy-vitamin D and 3-epi-25-hydroxy-vitamin D) in cell media with liquid chromatography-mass spectrometry-mass spectrometry. The mRNA expression (CYP27B1, CYP24A1 and CYP24A1-SV) was measured with qPCR. We found that reparative MDMs (M2a) had significantly more 1,25-dihydroxy-vitamin D compared to the other MDMs (M0, M1 and M2c). All MDMs were able to produce 3-epi-25-hydroxy-vitamin D, but this pathway was almost completely attenuated in inflammatory M1 MDMs. All MDM subtypes degraded vitamin D through the 24-hydroxylase pathway, although M1 MDMs mainly expressed an inactive splice variant of CYP24A1, coding the degrading enzyme. In conclusion, this study shows that vitamin D metabolism is highly dependent on macrophage polarization and that the C3-epimerase pathway for vitamin D is active in macrophages.
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Chau, Tsui-Shan, Wan-Ping Lai, Pik-Yuen Cheung, Murray J. Favus, and Man-Sau Wong. "Age-related alteration of vitamin D metabolism in response to low-phosphate diet in rats." British Journal of Nutrition 93, no. 3 (March 2005): 299–307. http://dx.doi.org/10.1079/bjn20041325.
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The responses of renal vitamin D metabolism to its major stimuli alter with age. Previous studies showed that the increase in circulating 1,25-dihydroxyvitamin D (1,25(OH)2D3) as well as renal 25-hydroxyvitamin D3 1-α hydroxylase (1-OHase) activity in response to dietary Ca or P restriction reduced with age in rats. We hypothesized that the mechanism involved in increasing circulating 1,25(OH)2D3 in response to mineral deficiency alters with age. In the present study, we tested the hypothesis by studying the expression of genes involved in renal vitamin D metabolism (renal 1-OHase, 25-hydroxyvitamin D 24-hydroxylase (24-OHase) and vitamin D receptor (VDR)) in young (1-month-old) and adult (6-month-old) rats in response to low-phosphate diet (LPD). As expected, serum 1,25(OH)2D3 increased in both young and adult rats upon LPD treatment and the increase was much higher in younger rats. In young rats, LPD treatment decreased renal 24-OHase (days 1–7, P<0·01) and increased renal 1-OHase mRNA expression (days 1–5, P<0·01). LPD treatment failed to increase renal 1-OHase but did suppress 24-OHase mRNA expression (P<0·01) within 7 d of LPD treatment in adult rats. Renal expression of VDR mRNA decreased with age (P<0·001) and was suppressed by LPD treatment in both age groups (P<0·05) Feeding of adult rats with 10 d of LPD increased 1-OHase (P<0·05) and suppressed 24-OHase (P<0·001) as well as VDR (P<0·05) mRNA expression. These results indicate that the increase in serum 1,25(OH)2D3 level in adult rats during short-term LPD treatment is likely to be mediated by a decrease in metabolic clearance via the down-regulation of both renal 24-OHase and VDR expression. The induction of renal 1-OHase mRNA expression in adult rats requires longer duration of LPD treatment than in younger rats.
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Gáll, Zsolt, and Orsolya Székely. "Role of Vitamin D in Cognitive Dysfunction: New Molecular Concepts and Discrepancies between Animal and Human Findings." Nutrients 13, no. 11 (October 20, 2021): 3672. http://dx.doi.org/10.3390/nu13113672.
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Purpose of review: increasing evidence suggests that besides the several metabolic, endocrine, and immune functions of 1alpha,25-dihydroxyvitamin D (1,25(OH)2D), the neuronal effects of 1,25(OH)2D should also be considered an essential contributor to the development of cognition in the early years and its maintenance in aging. The developmental disabilities induced by vitamin D deficiency (VDD) include neurological disorders (e.g., attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia) characterized by cognitive dysfunction. On the other hand, VDD has frequently been associated with dementia of aging and neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s disease). Recent findings: various cells (i.e., neurons, astrocytes, and microglia) within the central nervous system (CNS) express vitamin D receptors (VDR). Moreover, some of them are capable of synthesizing and catabolizing 1,25(OH)2D via 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1) and 25-hydroxyvitamin D 24-hydroxylase (CYP24A1) enzymes, respectively. Both 1,25(OH)2D and 25-hydroxyvitamin D were determined from different areas of the brain and their uneven distribution suggests that vitamin D signaling might have a paracrine or autocrine nature in the CNS. Although both cholecalciferol and 25-hydroxyvitamin D pass the blood–brain barrier, the influence of supplementation has not yet demonstrated to have a direct impact on neuronal functions. So, this review summarizes the existing evidence for the action of vitamin D on cognitive function in animal models and humans and discusses the possible pitfalls of therapeutic clinical translation.
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Fatemi, Seyed Abolghasem, Kenneth S. Macklin, Li Zhang, Ayoub Mousstaaid, Sabin Poudel, Ishab Poudel, and Edgar David Peebles. "Improvement in the Immunity- and Vitamin D3-Activity-Related Gene Expression of Coccidiosis-Challenged Ross 708 Broilers in Response to the In Ovo Injection of 25-Hydroxyvitamin D3." Animals 12, no. 19 (September 22, 2022): 2517. http://dx.doi.org/10.3390/ani12192517.
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Effects of the in ovo administration of two vitamin D3 sources (vitamin D3 (D3) and 25-hydroxyvitamin D3 (25OHD3)) on the expression of D3 activity- and immunity-related genes in broilers subjected to a coccidiosis infection were investigated. At 18 d of incubation (doi), five in ovo injection treatments were administrated to live embryonated Ross 708 broiler hatching eggs: non-injected (1) and diluent-injected (2) controls, or diluent injection containing 2.4 μg of D3 (3) or 2.4 μg of 25OHD3 (4), or their combination (5). Birds in the in ovo-injected treatments were challenged at 14 d of age (doa) with a 20× dosage of a live coccidial vaccine. At 14 and 28 doa, the expression of eight immunity-related genes (IL-2, IL-6, IL-10, TLR-4, TLR-15, MyD88, TGF-β4, and IFN-γ) and four D3 activity-related genes (1α-hydroxylase, 25-hydroxylase, 24-hydroxylase, and VDR) in the jejunum of one bird in each treatment–replicate group were evaluated. No significant treatment effects were observed for any of the genes before challenge. However, at 2 weeks post-challenge, the expression of 1α-hydroxylase, TGF-β4, and IL-10 increased in birds that received 25OHD3 alone in comparison to all the other in ovo-injected treatment groups. Additionally, the expression of 24-hydroxylase and IL-6 decreased in birds that received 25OHD3 in comparison to those injected with diluent or D3 alone. It was concluded that the in ovo injection of 2.4 μg of 25OHD3 may improve the intestinal immunity as well as the activity of D3 in Ross 708 broilers subjected to a coccidiosis challenge.
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van Driel, Marjolein van, and Johannes P. T. M. van van Leeuwen. "Vitamin D and Bone: A Story of Endocrine and Auto/Paracrine Action in Osteoblasts." Nutrients 15, no. 3 (January 17, 2023): 480. http://dx.doi.org/10.3390/nu15030480.
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Despite its rigid structure, the bone is a dynamic organ, and is highly regulated by endocrine factors. One of the major bone regulatory hormones is vitamin D. Its renal metabolite 1α,25-OH2D3 has both direct and indirect effects on the maintenance of bone structure in health and disease. In this review, we describe the underlying processes that are directed by bone-forming cells, the osteoblasts. During the bone formation process, osteoblasts undergo different stages which play a central role in the signaling pathways that are activated via the vitamin D receptor. Vitamin D is involved in directing the osteoblasts towards proliferation or apoptosis, regulates their differentiation to bone matrix producing cells, and controls the subsequent mineralization of the bone matrix. The stage of differentiation/mineralization in osteoblasts is important for the vitamin D effect on gene transcription and the cellular response, and many genes are uniquely regulated either before or during mineralization. Moreover, osteoblasts contain the complete machinery to metabolize active 1α,25-OH2D3 to ensure a direct local effect. The enzyme 1α-hydroxylase (CYP27B1) that synthesizes the active 1α,25-OH2D3 metabolite is functional in osteoblasts, as well as the enzyme 24-hydroxylase (CYP24A1) that degrades 1α,25-OH2D3. This shows that in the past 100 years of vitamin D research, 1α,25-OH2D3 has evolved from an endocrine regulator into an autocrine/paracrine regulator of osteoblasts and bone formation.
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Akeno, Nagako. "Cloning of Mouse 24-hydroxylase cDNA and Regulation of Vitamin D Metabolism in vivo." Japanese Journal of Oral Biology 41, no. 2 (1999): 91–97. http://dx.doi.org/10.2330/joralbiosci1965.41.91.
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