Incorportion of oxygen-18 into the 25-position of cholecalciferol by hepatic cholecalciferol 25-hydroxylase.
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ABSTRACT:
SUBMITTER: Madhok TC
PROVIDER: S-EPMC1186094 | biostudies-other | 1978 Nov
REPOSITORIES: biostudies-other
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Project description:Normal vitamin D homeostasis is critical for optimal health; nevertheless, vitamin D deficiency is a worldwide public health problem. Vitamin D insufficiency is most commonly due to inadequate cutaneous synthesis of cholecalciferol and/or insufficient intake of vitamin D, but can also arise as a consequence of pathological states such as obesity. Serum concentrations of 25(OH)D (calcidiol) are low in obesity, and fail to increase appropriately after vitamin D supplementation. Although sequestration of vitamin D in adipose tissues or dilution of ingested or cutaneously synthesized vitamin D in the large fat mass of obese patients has been proposed to explain these findings, here we investigate the alternative mechanism that reduced capacity to convert parent vitamin D to 25(OH)D due to decreased expression of CYP2R1, the principal hepatic vitamin D 25-hydroxylase. To test this hypothesis, we isolated livers from female mice of 6 to 24 weeks of age, weaned onto either a normal chow diet or a high-fat diet, and determined the abundance of Cyp2r1 mRNA using digital droplet-quantitative PCR. We observed a significant (p < 0.001) decrease in Cyp2r1 mRNA in the liver of high-fat diet-fed mice relative to lean-chow-fed female mice. Moreover, there was a significant (p < 0.01) relationship between levels of Cyp2r1 mRNA and serum 25(OH)D concentrations as well as between Cyp2R1 mRNA and the ratio of circulating 25(OH)D3 to cholecalciferol (p < 0.0001). Using linear regression we determined a curve with 25(OH)D3/cholecalciferol versus normalized Cyp2R1 mRNA abundance with an R2 value of 0.85. Finally, we performed ex vivo activity assays of isolated livers and found that obese mice generated significantly less 25(OH)D3 than lean mice (p < 0.05). Our findings indicate that expression of CYP2R1 is reduced in obesity and accounts in part for the decreased circulating 25(OH)D. © 2019 American Society for Bone and Mineral Research.
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Project description:Kinetics of vitamin D-depleted and -repleted rat liver microsomal cholecalciferol 25-hydroxylase were studied. Anaerobiosis, CO, omission of a NADPH-generating system and addition of detergents all decreased the activities, showing that the hydroxylase behaves like a cytochrome P-450-dependent enzyme. An apparent Km of 0.18 micrometer and Vmax. of 32pmol/min per g of tissue were found for vitamin D-deficient animals. Although both apparent Km and Vmax. were significantly altered in vitamin D-repleted animals no inhibition of the enzyme was elicited. These latter results show that at normal vitamin D intake, rat liver cholecalciferol 25-hydroxylase is not feedback-inhibited.
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Project description:Obesity is a major risk factor for several diseases including diabetes, heart disease, and some forms of cancer and due to its rapidly increasing prevalence it has become one of the biggest problems medicine is facing today. All the more surprising, a substantial percentage of obese patients are metabolically healthy when classified based on insulin resistance and systemic inflammation. Oxysterols are naturally occurring molecules that play important role in various metabolic and inflammatory processes and their levels are elevated in patients suffering from obesity and diabetes. 25-Hydroxycholesterol (25-OHC) is produced in cells from cholesterol by the enzyme cholesterol 25-hydroxylase (Ch25h) and is involved in lipid metabolism, inflammatory processes, and cell proliferation. Here, we investigated the role of hepatic Ch25h in the transition from metabolically healthy obesity to insulin resistance and diabetes. Using several different experimental approaches, we demonstrated the significance of Ch25h on the border of "healthy" and "diseased" states of obesity. Adenovirus-mediated Ch25h overexpression in mice improved glucose tolerance and insulin sensitivity and lowered HOMA-IR. Our data suggest that low hepatic Ch25h levels could be considered a risk marker for unhealthy obesity.
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Project description:Recent understanding of extrarenal production of calcitriol has led to the exploration of native vitamin D treatment in dialysis patients. This paper reports the pharmacokinetics of 25-hydroxyvitamin D response to 10,333 IU cholecalciferol given weekly in subjects on chronic dialysis.This randomized, double-blind, placebo-controlled trial of 15 weeks of oral cholecalciferol in subjects with stage 5 CKD requiring maintenance hemodialysis was conducted from November of 2007 to March of 2010. The time course of serum 25-hydroxyvitamin D was measured over the course of treatment. Additionally, blood was drawn at baseline and last visit for calcium, phosphorus, calcitriol, and parathyroid hormone levels.The median (interquartile range) baseline 25-hydroxyvitamin D level was 13.3 (11.1-16.2) ng/ml for the treatment group and 15.2 (10.7-19.9) ng/ml for the placebo group. 25-hydroxyvitamin D steady state levels rose by 23.6 (19.2-29.9) ng/ml in the treatment group, and there was no change in the placebo group. Calcitriol levels also increased significantly in the treatment group. There were no significant changes in levels of calcium, albumin, phosphorus, and parathyroid hormone in either group.Cholecalciferol (10,333 IU) given weekly in patients on chronic hemodialysis produces a steady state in 25-hydroxyvitamin D of approximately 24 ng/ml.
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Project description:According to RNA-seq results, application of vitamin D in the form of 25(OH)D in swine diet can be beneficial for myogenesis, energy production and muscle fibre formation by influencing TOR signalling pathway. However, the use of vitamin D in the form of 25(OH)D may reduce muscle respiratory capacity.
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Project description:This pilot clinical trial studies cholecalciferol in treating patients with colorectal cancer. The use of cholecalciferol may slow disease progression in patients with colorectal cancer.
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Project description:Patients with chronic kidney disease (CKD) demonstrate complex mineral metabolism derangements and a high prevalence of vitamin D deficiency. However, the optimal method of 25-hydroxyvitamin D (25(OH)D) repletion is unknown, and trials analysing the comparative efficacy of cholecalciferol and ergocalciferol in this population are lacking. We conducted a randomised clinical trial of cholecalciferol 1250?g (50 000 IU) weekly v. ergocalciferol 1250?g (50 000 IU) weekly for 12 weeks in forty-four non-dialysis-dependent patients with stage 3-5 CKD. The primary outcome was change in total 25(OH)D from baseline to week 12 (immediately after therapy). Secondary analyses included the change in 1,25-dihydroxyvitamin D (1,25(OH)2D), parathyroid hormone (PTH), D2 and D3 sub-fractions of 25(OH)D and 1,25(OH)2D and total 25(OH)D from baseline to week 18 (6 weeks after therapy). Cholecalciferol therapy yielded a greater change in total 25(OH)D (45·0 (sd 16·5) ng/ml) v. ergocalciferol (30·7 (sd 15·3) ng/ml) from baseline to week 12 (P<0·01); this observation partially resulted from a substantial reduction in the 25(OH)D3 sub-fraction with ergocalciferol. However, following cessation of therapy, no statistical difference was observed for total 25(OH)D change from baseline to week 18 between cholecalciferol and ergocalciferol groups (22·4 (sd 12·7) v. 17·6 (sd 8·9) ng/ml, respectively; P=0·17). We observed no significant difference between these therapies with regard to changes in serum PTH or 1,25(OH)2D. Therapy with cholecalciferol, compared with ergocalciferol, is more effective at raising serum 25(OH)D in non-dialysis-dependent CKD patients while active therapy is ongoing. However, levels of 25(OH)D declined substantially in both arms following cessation of therapy, suggesting the need for maintenance therapy to sustain levels.
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Project description:Studies of 25-hydroxyvitamin D(3)-24-hydroxylase (CYP24A1) have demonstrated that it is a bifunctional enzyme capable of the 24-hydroxylation of 1alpha,25-(OH)(2)D(3), leading to the excretory form, calcitroic acid, and 23-hydroxylation, culminating in 1alpha,25-(OH)(2)D(3)-26,23-lactone. The degree to which CYP24A1 performs either 23- or 24-hydroxylation is species-dependent. In this paper, we show that the human enzyme that predominantly 24-hydroxylates its substrate differs from the opossum enzyme that 23-hydroxylates it at only a limited number of amino acid residues. Mutagenesis of the human form at a single substrate-binding residue (A326G) dramatically changes the regioselectivity of the enzyme from a 24-hydroxylase to a 23-hydroxylase, whereas other modifications have no effect. Ala-326 is located in the I-helix, close to the terminus of the docked 25-hydroxylated side chain in a CYP24A1 homology model, a result that we interpret indicates that substitution of a glycine at 326 provides extra space for the side chain of the substrate to move deeper into the pocket and place it in a optimal stereochemical position for 23-hydroxylation. We discuss the physiological ramifications of these results for species possessing the A326G substitution, as well as implications for optimal vitamin D analog design.
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Project description:Interferons (IFN) are essential antiviral cytokines that establish the cellular antiviral state through upregulation of hundreds of interferon-stimulated genes (ISGs), most of which have uncharacterized functions and mechanisms. We identified cholesterol-25-hydroxylase (CH25H) as a broadly antiviral ISG. CH25H converts cholesterol to a soluble antiviral factor, 25-hydroxycholesterol (25HC). 25HC treatment in cultured cells broadly inhibited growth of enveloped viruses including VSV, HSV, HIV, and MHV68 and acutely pathogenic EBOV, RVFV, RSSEV, and Nipah viruses under BSL4 conditions. It suppressed viral growth by blocking membrane fusion between virus and cell. In animal models, Ch25h-deficient mice were more susceptible to MHV68 lytic infection. Moreover, administration of 25HC in humanized mice suppressed HIV replication and reversed T cell depletion. Thus, our studies demonstrate a unique mechanism by which IFN achieves its antiviral state through the production of a natural oxysterol to inhibit viral entry and implicate membrane-modifying oxysterols as potential antiviral therapeutics.
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Project description:ContextVitamin D deficiency disproportionately affects nonwhite individuals. Controversy persists over how to best restore low 25D levels, and how to best define vitamin D status [total (protein bound plus free) vs free 25D].ObjectiveTo assess the effects of vitamin D3 (cholecalciferol, or D3) vs 25-hydroxyvitamin D3 (calcifediol, or 25D3) on total and free 25D in a multiethnic cohort of adults, and whether change in parathyroid hormone (PTH) is more strongly associated with total vs free 25D.DesignSixteen-week randomized controlled trial. Biochemistries at 0, 4, 8, and 16 weeks.SettingAcademic medical center.ParticipantsThirty-five adults ≥18 years of age with 25D levels <20 ng/mL.InterventionSixty micrograms (2400 IU)/d of D3 or 20 μg/d of 25D3.Main outcome measuresTotal and free 25D, and PTH.ResultsBaseline total (16.2 ± 3.7 vs 17.0 ± 2.5 ng/mL; P = 0.4) and free (4.2 ± 0.8 vs 4.7 ± 1.0 pg/mL; P = 0.2) 25D were similar between D3 and 25D3 groups, respectively; 25D3 increased total (+25.5 vs +13.8 ng/mL; P = 0.001) and free (+6.6 vs +3.5 pg/mL; P = 0.03) 25D more than D3. By 4 weeks, 87.5% of 25D3 participants had total 25D levels ≥30 ng/mL, compared with 23.1% of D3 participants (P = 0.001). Change in PTH was associated with both total (P = 0.01) and free 25D (P = 0.04).Conclusions25D3 increased total and free 25D levels more rapidly than D3, regardless of race/ethnicity. Free and total 25D were similarly associated with change in PTH.
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