Impaired release of Vitamin D in dysfunctional adipose tissue: New cues on Vitamin D supplementation in obesity

Context: Vitamin D accumulates in adipose tissue (AT) and vitamin D deficiency is frequent in obesity. Objective: We hypothesize that trafficking of vitamin D is altered in dysfunctional AT. Design, Patients, Settings: 54 normal-weight and 67 obese males were recruited in a prospective study and randomly assigned to supplementation with 50 \ub5g/week 25-hydroxyvitamin-D3 (25(OH)D) or 150 \ub5g/week vitamin D3 for 1 year, raising dosage by 50% if vitamin D-sufficiency (serum 25(OH)D>50 nomol/l), was not achieved at 6 months; 97 subjects completed the study. Methods: Vitamin D3 (D3) and 25(OH)D were quantified by HPLC-MS in control and insulin-resistant (IR) 3T3-L1 cells and subcutaneous AT (SAT) from lean and obese subjects, incubated with or without adrenaline; expression of 25-hydroxylase (CYP27A1), 1\u3b1-hydroxylase (CYP27B1) and vitamin D receptor (VDR) were analysed by real-time PCR. Results: In IR adipocytes the uptake of D3 and 25(OH)D was higher, but after adrenaline stimulation, the decrement in D3 and 25(OH)D was stronger in control cells, which also showed increased expression of CYP27A1 and CYP27B1 and higher levels of 25(OH)D. In SAT from obese subjects, the adrenaline-induced release of D3 and 25(OH)D was blunted; in both IR cells and obese SAT, protein expression of \u3b22-adrenergic receptor was reduced. Supplementation with 25-hydroxyvitamin-D3 was more effective in achieving vitamin D sufficiency in obese, but not in normal weight subjects. Conclusion: Dysfunctional AT shows a reduced catecholamine-induced release of D3 and 25(OH)D, and altered activity of vitamin D-metabolizing enzymes, for these reasons supplementation with 25-hydroxyvitamin-D3 is more effective in obese individuals

Vitamin D dependent rickets type I

Vitamin D is present in two forms, ergocalciferol (vitamin D2) produced by plants and cholecalciferol (vitamin D3) produced by animal tissues or by the action of ultraviolet light on 7-dehydrocholesterol in human skin. Both forms of vitamin D are biologically inactive pro-hormones that must undergo sequential hydroxylations in the liver and the kidney before they can bind to and activate the vitamin D receptor. The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D], plays an essential role in calcium and phosphate metabolism, bone growth, and cellular differentiation. Renal synthesis of 1,25(OH)2D from its endogenous precursor, 25-hydroxyvitamin D (25OHD), is the rate-limiting and is catalyzed by the 1α-hydroxylase. Vitamin D dependent rickets type I (VDDR-I), also referred to as vitamin D 1α-hydroxylase deficiency or pseudovitamin D deficiency rickets, is an autosomal recessive disorder characterized clinically by hypotonia, muscle weakness, growth failure, hypocalcemic seizures in early infancy, and radiographic findings of rickets. Characteristic laboratory features are hypocalcemia, increased serum concentrations of parathyroid hormone (PTH), and low or undetectable serum concentrations of 1,25(OH)2D despite normal or increased concentrations of 25OHD. Recent advances have showed in the cloning of the human 1α-hydroxylase and revealed mutations in its gene that cause VDDR-I. This review presents the biology of vitamin D, and 1α-hydroxylase mutations with clinical findings

Up-regulation of vitamin D system in adipocytes by macrophage-derived factors: implications for (patho)physiology of adipose tissue

Vitamin D3 (cholecalciferol) plays an important role in calcium, phosphate, and bone metabolism. Vitamin D3, either synthesized endogenously or derived from alimentary sources, is first activated through sequential hydroxylations by vitamin D3 25-hydroxylase in the liver and 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1) in the kidney to 25-OH-D3 and 1,25(OH)2D3 (calcitriol), respectively. Calcitriol - the active vitamin D derivative - regulates calcium metabolism by acting on nuclear and extranuclear vitamin D receptors (VDR). Apart from mineral metabolism, vitamin D is involved in many other processes such as cell proliferation, inflammatory and immune reactions, glucose and lipid metabolism, etc. Indeed, VDR are expressed in virtually all tissues and vitamin D deficiency is suggested to contribute to the pathogenesis of various diseases including certain types of cancer, inflammatory bowel disease, multiple sclerosis, periodontal diseases, diabetes, hypertension, atherosclerosis and neurodegenerative diseases. In addition, vitamin D supplementation is beneficial in humans with at least some of these disorders and in animal experimental models of them.Adipobiology 2011; 3: 37-38

Pleiotropic Effects of Vitamin D in Kidney Disease

Vitamin D is metabolized in the liver and kidneys and then converted to the active form, 1.25-dihydroxyvitamin D [1.25(OH)2D]. Chronic kidney disease patients usually lack both 25-hydroxyvitamin D [25(OH)D] and 1.25(OH)2D due to impaired renal function and 1α-hydroxylase deficiency. Chronic kidney disease patients have a high incidence of cardiovascular and infectious morbidities. Increasing evidence indicates a relationship between vitamin D deficiency and cardiovascular and infectious mortality risks. Vitamin D may have significant biological effects beyond its traditional roles on mineral and bone metabolism. Many extrarenal cells have the capability to produce local active 1.25(OH)2D in an intracrine or paracrine fashion. Vitamin D has a significant association with nonskeletal diseases, such as immunodeficiency, metabolic syndrome, insulin resistance, diabetes, hyperlipidemia, cardiovascular disease, proteinuria, and acute kidney injury. This article aims to review and summarize the pleiotropic effects of vitamin D in patients with kidney disease, particularly the immunological, metabolic, cardiovascular, and renal effects

Vitamin D and Female Reproduction

Vitamin D deficiency has an impact on the reproduction of more than 40% of reproductive age women globally. Fibroids are more common among African-American females owing to their decreased milk consumption and reduced absorption of ultraviolet rays, supporting the relation between vitamin D deficiency and fibroid development. Vitamin D has an inhibitory effect on leiomyoma cells by suppression of proliferation cell nuclear antigen (PCNA), BCL-2, BCL-w, CDK1, and catechol-O-methyltransferase (COMT) protein levels. A growing evidence support the relationship between vitamin D deficiency and endometriosis through overexpression of vitamin D recseptor (VDR) and α-hydroxylase enzyme, however, it is still unclear if the endometriosis patients could benefit from vitamin D supplementation. Effect of vitamin D supplementation on the metabolic outcomes of polycystic ovary (PCO) has been studied and reveled that it is negatively correlated with fasting glucose, fasting insulin, triglycerides, C-reactive protein, free androgen index, and Dehydroepiandrosterone (DHEAS) and positively associated with quantitative insulin sensitivity check index (QUICKI), high density lipoprotein cholesterol (HDL-C), and sexual hormone binding globulin (SHBG), whereas its impact on the ovarian function is still unclear. Vitamin D deficiency may worse the obstetrical outcomes, including preeclampsia, gestational diabetes, low birth weight, increased cesarean section rate, neonatal asthma, seizures, and preterm labor. The relationship between serum levels of 25-hydroxy-vitamin D (25(OH) D) and pregnancy rates in ART is still debatable, with the need to conduct more clinical trials toward it. The in vitro antiproliferative and prodifferentiative effect of vitamin D might find a role in control of hyperplastic overactive bladder. Several studies support that vitamin D deficiency constitutes a risk factor for development of many types of cancer such as breast, ovarian, and colorectal

High prevalence of vitamin D deficiency among women of child-bearing age in Lahore Pakistan, associating with lack of sun exposure and illiteracy

BACKGROUND: Vitamin D status is a key determinant of maternal and neonatal health. Deficiency has been reported to be common in Pakistani women, but information regarding environmental and genetic determinants of vitamin D status is lacking in this population. METHODS: We conducted a cross-sectional study among three groups of healthy women living in Lahore, Pakistan: university students, students or employees of Medrasas or Islamic Institutes, and employees working in office, hospital or domestic settings. Multivariate analysis was performed to identify environmental and genetic determinants of vitamin D status: polymorphisms in genes encoding the vitamin D receptor, vitamin D 25-hydroxylase enzyme CYP2R1 and vitamin D binding protein [DBP] were investigated. We also conducted analyses to identify determinants of body ache and bone pain in this population, and to determine the sensitivity and specificity of testing for hypocalcaemia and raised serum alkaline phosphatase to screen for vitamin D deficiency. RESULTS: Of 215 participants, 156 (73 %) were vitamin D deficient (serum 25[OH]D <50 nmol/L). Risk of vitamin D deficiency was independently associated with illiteracy (adjusted OR 4.0, 95 % CI 1.03–15.52, P = 0.04), <30 min sun exposure per day (adjusted OR 2.13, 95 % CI 1.08–4.19, P = 0.02), sampling in January to March (adjusted OR 2.38, 95 % CI 1.20–4.70), P = 0.01) and lack of regular intake of multivitamins (adjusted OR 2.61, 95 % CI 1.32–5.16, p = 0.005). Participants with the GG genotype of the rs4588 polymorphism in the gene encoding vitamin D binding protein tended to have lower 25(OH)D concentrations than those with GT/TT genotypes (95 % CI for difference 22.7 to −0.13 nmol/L, P = 0.053). Vitamin D deficiency was independently associated with increased risk of body ache or bone pain (adjusted OR 4.43, 95 % CI 2.07 to 9.49, P = 0.001). Hypocalcaemia (serum calcium concentration ≤9.5 mg/dL) and raised alkaline phosphatase concentration (≥280 IU/L) had low sensitivity and very low specificity for identification of vitamin D deficiency. CONCLUSION: Vitamin D deficiency is common among healthy women of child-bearing age in Lahore, Pakistan: illiteracy, decreased sun exposure and lack of multivitamin intake are risk factors

A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report

BACKGROUND: Rickets can occur due to Vitamin D deficiency or defects in its metabolism. Three rare genetic types of rickets with different alterations of genes have been reported, including: Vitamin D dependent rickets type 1, Vitamin D dependent rickets type 2 or also known as Vitamin D resistant rickets and 25 hydroxylase deficiency rickets. Vitamin D dependent rickets type 1 is inherited in an autosomal recessive pattern, and is caused by mutations in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. We report here a new mutation in CYP27B1, which lead to Vitamin D dependent rickets type 1. CASE PRESENTATION: We report on a 13-month-old Arabic Saudi girl with Vitamin D dependent rickets type 1 presented with multiple fractures and classic features of rickets. A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration. Both parents are heterozygous carriers of the mutation. Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory). CONCLUSION: The deleterious effect of this alteration, which was the only mutation detected in the CYP27B1 common gene of Vitamin D dependent rickets type 1 in the proband, and its autosomal recessive inheritance fashion, both support a pathogenic nature of this mutation as the cause of Vitamin D dependent rickets type 1

D Vitamini Yetersizliği ve Depresyon: Ne Yapabiliriz?

Vitamin D deficiency is known to be widely in Western populations. The implications of this in terms of bone health are increasingly understood, yet its impact on other health areas, particularly mental health, is unclear. Although recent data shown that vitamin D has an important impact on pathophysiology and progression of serious chronic illness, vitamin D deficiency may be common, especially in the risk groups who utilize limited sunshine such as elderly, pregnant and children. Low vitamin D levels are associated with depression, poor mood and other mental disorders. Most important data about relationship between vitamin D and depression is determination of vitamin D receptors at most area in brain and immüno reactivity of 1-alpha-hydroxylase that convert to 1.25(OH)D from 25(OH). Although there are a number of trials that have suggested a role on lower serum vitamin D level and pathophysiology of depression, more studies were need about vitamin D supplementation on treatment of depression. Vitamin D deficiency is still major public health problem for our country. Primarycare patients with a history of depression may be an important target for assessment of vitamin D levels

Vitamin D metabolism in the fruit bat (Rousettus aegyptiacus)

A dissertation submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg for the Degree of Masters of Science. December 1992.Rouesettus aegyptiacus, the fruit bat is a crepuscular frugivore with no obvious access to either exogenous or endogenous sources of vitamin D. Therefore this animal's vitamin D status and endocrine system was investigated. Both captive and wild populations of fruit bats appear to be naturally in a vitamin D impoverished state. The serum concentration of the principle circulatory, metabolite [25(OH)D] is undetectable (< 4 ng/ml), Fruit bats possess the full compliment of enzymes associated with the vitamin D endocrine system. This was shown when labelled more polar metabolites were produced after the administration of 3H vitamin D3 and 3H 2S(OH)D3' Furthermore, a specific vitamin D binding protein (DBP) is present. After partial purification, it was revealed that this molecule is slightly larger in molecular mass than that of humans and baboons. The intraperitoneal administration of 25(OH)D3 revealed enhanced 1a-hydroxylase activity such that 1.7 times more 1,25(OH)2Ds was produced than 24,25(OH)2D3' The ratio of these di-hydroxylated metabolites conform with the ratio of these 2 metabolites in states of vitamin D deficiency and thus confirm the impoverished vitamin D status. Undetectable serum concentrations of 25(OH)D3 might therefore be explained by a limited exogenous vitamin D substrate (rotting fruit peels and fungi). Given the elevated 1a hydroxylase activity 1 the small amount'S of 25(OH)D produced would be rapidly converted to the active metabolite. The low concentration of active hormone appear adequate for the maintenance of mineral homeostasis as indicated by tightly controlled serum calcium (2.26 ± 0.17 mrnol/l), magnesium 01.16 + 0.24 mmol/l) and inorganic phosphorus (2.93 ± 1.01 mmol/I). Both vitamin D2 and vitamin D3 metabolites were detected in bat serum albeit in very small amounts, suggesting that fruit bats exploit both exogenous plant sources (skins of fruit - vitamin 1)2; fungi - vitamin D:3)and might indeed receive some U. V. light during their crepuscular forays to endogenously produce small amounts of vitamin D3 In conclusion, fruit bats appear to belong to a small group of animals that naturally have limited access to Vitamin D, yet the vitamin D endocrine system in these animals is no different to that of other mammals. These animals have adapted their vitamin D endocrine system to function well at the low hormone concentrations and they exhibit no pathological problems associated with relative vitamin D depletion.AC201

Impact of vitamin D in chronic kidney disease and its effect on the musculoskeletal system

Abstract Introduction. Vitamin D plays an important role in maintaining musculoskeletal health. As the glomerular filtration rate decreases, vitamin D deficiency also occurs. The aim of this paper is to highlight the level of vitamin D depending on the stage of chronic kidney disease. Materials and methods. A structured search was performed in the PubMed, Scopus and HINARI databases, where the relevant articles have been taken into account, published in the last 20 years. The search terms used (in English) were: „vitamin D deficiency”, „pathogenesis of vitamin D”, ”the impact of vitamin D in chronic kidney disease”, „chronic kidney disease”. Results. Several studies have shown that the change in vitamin D levels is dependent to the decrease of glomerular filtration rate. The lowest serum vitamin D concentration was observed in stage 5 of chronic kidney disease. Vitamin D deficiency occurs due to a decrease in the number of nephrons and a decrease in the number of proximal tubular cells that absorb vitamin D (25 (OH) D) to be subsequently hydroxylated to its active form by 1α-hydroxylase. Conclusions. Patients with vitamin D-deficient due to chronic kidney disease have an increased risk of decreased bone mineral density and multiple fracture