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BACKGROUND/OBJECTIVES: The aim was to examine the causal effect of vitamin D on serum adiponectin using a multiple instrument Mendelian randomization approach. SUBJECTS/METHODS: Serum 25-hydroxy vitamin D (25(OH)D) and serum total or high molecular weight (HMW) adiponectin were measured in two Danish population-based studies: the Inter99 study (6405 adults, 30-60 years) conducted in 1999-2001, and the MONICA10 study (2656 adults, 41-71 years) conducted in 1993-1994. RESULTS: In the Inter99 study, serum 25(OH)D was positively associated with total adiponectin (the effect estimate in % per doubling of 25(OH)D was 4.78, 95% CI: 1.96, 7.68, P CONCLUSIONS: The results indicate a possible causal association between serum 25(OH)D and total adiponectin. However, the association was not replicated for HMW adiponectin. Thus, further studies are needed to confirm a causal relationship. European Journal of Clinical Nutrition (2014) 68, 189-195; doi: 10.1038/ejcn.2013.233; published online 13 November 2013 Keywords: causation; filaggrin; instrumental variables; rs2282679; 25-hydroxy vitamin D; adipokines, INTRODUCTION It is suggested that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance and development of type 2 diabetes. (1,2) The mechanism by which vitamin D may affect [...]

The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25[(OH).sub.2][D.sub.3] transcriptionally suppresses renin gene expression has been elucidated; however, how vitamin D regulates AGT remains unknown. Exposure of mesangial cells or podocytes to high glucose (HG; 30 mM) markedly stimulated AGT expression. In mesangial cells, the stimulation was inhibited by 1,25[(OH).sub.2][D.sub.3] (20 nM) or NF-[kappa]B inhibitor BAY 11-7082, suggesting the involvement of NF-[kappa]B in HG-induced AGT expression and the interaction between 1,25[(OH).sub.2][D.sub.3] and NF-[kappa]B in the regulation. Plasmid pNF-[kappa]B-Luc luciferase reporter assays showed that 1,25[(OH).sub.2][D.sub.3] blocked HG-induced NF-[kappa]B activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-[kappa]B binding site at--1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25[(OH).sub.2][D.sub.3] treatment. Overexpression of p65/p50 overcame 1,25[(OH).sub.2][D.sub.3] suppression, and mutation of this NF-[kappa]B binding site blunted 1,25[(OH).sub.2][D.sub.3] suppression of the promoter activity. In mice lacking the vitamin D receptor, AGT mRNA expression in the kidney was markedly increased compared with wild-type mice, and AGT induction in diabetic mice was suppressed by treatment with a vitamin D analog. These data indicate that 1,25[(OH).sub.2][D.sub.3] suppresses hyperglycemia-induced AGT expression by blocking NF-[kappa]B-mediated pathway. vitamin D receptor; renin-angiotensin system; diabetic nephropathy

Tuberculosis is highly prevalent worldwide, accounting for nearly two million deaths annually. Vitamin D influences the immune response to tuberculosis, and vitamin D deficiency has been associated with increased tuberculosis risk in different populations. Genetic variability may influence host susceptibility to developing active tuberculosis and treatment response. Studies examining the association between genetic polymorphisms, particularly the gene coding for the vitamin D receptor (VDR), and TB susceptibility and treatment response are inconclusive. However, sufficient evidence is available to warrant larger epidemiologic studies that should aim to identify possible interactions between VDR polymorphisms and vitamin D status.

Recent studies have established that vitamin D plays multiple biological roles beyond calcium metabolism; however, whether vitamin D is involved in energy metabolism is unknown. To address this question, we characterized the metabolic phenotypes of vitamin D receptor (VDR)-null mutant mice. Under a normocalcemic condition, VDR-null mice displayed less body fat mass and lower plasma triglyceride and cholesterol levels compared with wild-type (WT) mice; when placed on a high-fat diet, VDR-null mice showed a slower growth rate and accumulated less fat mass globally than WT mice, even though their food intake and intestinal lipid transport capacity were the same as WT mice. Consistent with the lower adipose mass, plasma leptin levels were lower and white adipocytes were histologically smaller in VDR-null mice than WT mice. The rate of fatty acid [beta]-oxidation in the white adipose tissue was higher, and the expression of uncoupling protein (UCP) 1, UCP2 and UCP3 was markedly upregulated in VDR-null mice, suggesting a higher energy expenditure in the mutant mice. Experiments using primary brown fat culture confirmed that 1,25-dihydroxyvitamin [D.sub.3] directly suppressed the expression of the UCPs. Consistently, the energy expenditure, oxygen consumption, and C[O.sub.2] production in VDR-null mice were markedly higher than in WT mice. These data indicate that vitamin D is involved in energy metabolism and adipocyte biology in vivo in part through regulation of [beta]-oxidation and UCP expression. adipocytes; uncoupling proteins; energy metabolism

Objective: To assess the genetic and nongenetic correlates of circulating measures of vitamins K and D status in a community-based sample of men and women. Subjects/Methods: A cross-sectional study of 1762 participants of the Framingham Offspring Study (919 women; mean age 59 years). Vitamin K status was measured as plasma phylloquinone and serum percent undercarboxylated osteocalcin (ucOC), and vitamin D was measured using plasma 25-hydroxyvitamin D (25(OH)D). Associations between vitamin K status and vitamin D status with biologically plausible nongenetic factors were assessed using stepwise regression. Heritability and linkage were determined using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Results: Nongenetic factors accounted for 20.1 and 12.3% of the variability in plasma phylloquinone in men and women respectively, with triglycerides and phylloquinone intake being the primary correlates. In men 12.2% and in women 14.6% of the variability in %ucOC was explained by nongenetic factors in our models. Heritability estimates for these vitamin K status biomarkers were nonsignificant. Season, vitamin D intake, high-density lipoprotein (HDL) cholesterol and waist circumference explained 24.7% (men) and 24.2% (women) of the variability in plasma 25(OH)D. Of the three vitamins examined, only 25(OH)D was significantly heritable (heritability estimate = 28.8%, P Conclusions: Variability in biomarkers of vitamin K status was attributed to nongenetic factors, whereas plasma 25(OH)D was found to be significantly heritable. Further studies are warranted to investigate genetic loci influencing vitamin D status. doi:10.1038/sj.ejcn.1602959; published online 21 November 2007 Keywords: vitamin K; phylloquinone; undercarboxylated osteocalcin; vitamin D; heritability; genetics, Introduction Vitamins K and D are two nutrients involved in bone health (Cockayne et al., 2006). Vitamin K functions as a cofactor in the y-carboxylation of specific proteins, of which [...]

The classic role of vitamin D has involved its function in calcium metabolism. However, a much broader perspective of the importance of vitamin D is now emerging. Therefore, a new approach is needed based on a combination of molecular biological, physiological, and clinical/epidemiological studies. The remarkable range of the effects of vitamin D relates to our new understanding of both the role of the vitamin D receptor and analyses of what might be considered an optimum vitamin D status in populations exposed to very different diets and levels of sun exposure. Assessing the breadth of the current approaches was the basis of the 22nd Marabou Symposium that took place in Stockholm in June 2007. The complete proceedings will be presented in this journal as a supplement to an upcoming issue.

Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1[alpha] (TIF1[alpha]), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1[alpha] is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1[alpha] resemble those seen in mice carrying an activating mutation of the calcium sensor receptor (Casr) gene and, in TIF1[alpha]-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2, Cyp24a1, Trpv5, Trpv6, Calb1, S100g, Pthlh, and Spp1. Thus, our data indicate that TIF1[alpha] represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1[alpha] deficiency. Interestingly, the calcifying arteriopathy of TIF1[alpha]-null mutant mice shares features with the human age-related Monckeberg's disease and, overall, the TIF1[alpha]-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway. aging | ectopic calcification | mouse knockout | transcriptional regulation | vitamin D signaling

Lactation-associated bone loss has been reported in adolescent mothers. Polymorphisms in the vitamin D receptor (VDR) gene may contribute to differences in the physiologic skeletal response to lactation in these mothers. We evaluated the influence of VDR gene polymorphisms Apal, Bsml, and Taql on bone mass, bone and calcium-related hormones, and breast milk calcium of lactating adolescents with habitually low calcium intake. Total body bone mineral content (TBMC), total body bone mineral density (TBMD), lumbar spine BMD (LSBMD), serum hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, insulin-like growth factor-I (IGF1), prolactin, and estradiol), and breast milk calcium were measured in 40 lactating Brazilian adolescents (15-18 y), and compared by VDR genotype subgroups after adjustment for calcium intake and postmenarcheal and lactational periods. TBMD and LSBMD Zscores were -0.55 [+ or -] 1.01 and -1.15 [+ or -] 1.48, respectively. LSBMD was higher (21%; P < 0.05) in adolescents with the aa genotype (n = 5) compared with those with the AA genotype (n = 7). TBMC and IGF1 were higher (23 and 50%, respectively; P < 0.05) in adolescents with tt (n = 4) than those with TT(n = 29) and Tt (n = 7) genotypes. Breast milk calcium and serum iPTH were higher (24 and 80%, respectively; P < 0.05) in adolescents with bb (n = 8) compared with those with BB (n = 21) genotype. These results indicate that bone mass and breast milk calcium are significantly associated with VDR genotypes in lactating Brazilian adolescents. Those with aa and tt genotypes had a better bone status and those with bb genotype had greater breast milk calcium.

Renal vitamin D receptor (VDR) is required for 1,25-dihydroxyvitamin [D.sub.3-][1,25(OH[).sub.2][D.sub.3]]-induced renal reabsorption of calcium and for 1,25(OH[).sub.2][D.sub.3]-induced 1,25(OH[).sub.2][D.sub.3] 24-hydroxylase. The longterm effect of vitamin D and dietary calcium on the expression of renal VDR was examined in the nonobese diabetic mouse. Vitamin D-deficient and vitamin D-replete mice were maintained on diets containing 0.02%, 0.25%, 0.47%, and 1.20% calcium with or without 50 ng of 1,25(OH[).sub.2][D.sub.3] per day. Vitamin D-replete mice on a 1.20% calcium diet had renal VDR levels of 165 fmol/mg protein. Calcium restriction caused renal VDR levels to decrease to

The effects of 1,25-dihydroxyvitamin [D.sub.3] [1,25-[(OH).sub.2][D.sub.3]] are mediated by the vitamin D receptor (VDR), a member of the nuclear receptor superfamily of transcriptional regulators. We have identified upstream exons of the human (h) VDR gene that are incorporated into variant transcripts, two of which encode N-terminal variant receptor proteins. Expression of the hVDR gene, which spans more than 60 kb and consists of at least 14 exons, is directed by two distinct promoters. A tissue-specific distal promoter generates unique transcripts in tissues involved in calcium regulation by 1,25-[(OH).sub.2][D.sub.3] and can direct the expression of a luciferase reporter gene in a cell line-specific manner. These major N-terminal differences in hVDR transcripts, potentially resulting in structural differences in the expressed receptor, may contribute to cellular responsiveness to 1,25[(OH).sub.2][D.sub.3] through tissue differences in the regulation of VDR expression.

Osteoporosis is related to a new concept of normal gene variants and physiological variation developed relative to vitamin D polymorphisms and calcium homeostasis. The genetics of osteoporosis has been related to targeting genetic studies, and genome scan approaches may be used in time. Relationships between environment, lifestyle, and genetics may be a topic for research in the future, and more specific treatments and better options may emerge.

The gene encoding the mouse vitamin D receptor has been cloned. A new exon 1 has been found that changes the numbering established for the human VDR gene. Exons 2 and 3 in the human VDR gene (coding for the zinc fingers 1 and 2, respectively) are named exons 3 and 4 in the mouse vitamin D receptor. The 1.5-kb 5[prime]-flanking region of the new exon 1 was analyzed and revealed the presence of putative cis-acting elements. Despite the absence of a TATA box, this 5[prime]-flanking region contains several characteristics of a GC-rich promoter including four Sp1 sites present in tandem and two CCAAT boxes. Interestingly, the Sp1 site that is the most proximal to the new exon 1 overlaps a perfect site for Krox-20/24. Krox-20 is a transcription factor involved in brain development, and also in bone remodeling. In luciferase reporter gene expression assays, we showed that sequences from this 5[prime]-flanking region elicit high transactivation activity. Furthermore, in the NIH 3T3 cell line, a 3- to 5-fold increase in response to forskolin treatment (an activator of adenylate cyclase and in turn of protein kinase A pathway) was observed.

The trans-acting factors associated with the basal and hormone-responsive elements in the rat osteocalcin (OC) gene promoter were investigated. The results showed that AP-1 binding is inhibited postproliferatively with concomitant modifications in transcription factor complexes at vitamin D-responsive regulatory elements. These results indicate that AP-1 activity is involved in the regulation of the developmental expression the OC gene.

A vitamin D receptor-specific probe was used to assess the restriction fragment length polymorphism (RFLP) profile of 288 subjects to determine possible correlations between vitamin D receptor variability and osteocalcin levels. The results showed that frequently occuring RFLP markers at the vitamin D receptor locus on chromosome 12 are highly correlated with the serum levels of osteocalcin. These results indicate that these different RFLPs correspond to different functional alleles of the vitamin D receptor.

The Id protein is a member of the helix-turn-helix family, which are involved in the differentiation of several cell types. An investigation was conducted to determine if Id is expressed in the ROS17/2.8 osteoblastic cell line. Northern blot experiments showed that Id is expressed in ROS17/2.8 constitutively, and is regulated by vitamin D in a dose-dependent manner. Nuclear run-on experiments indicate that vitamin D acts on a transcriptional level, suggesting the presence of vitamin D response elements in the Id gene.

Balesaria S, Sangha S, Waiters JR. Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption. Am J Physiol Gastrointest Liver Physiol 297: G1193-G1197, 2009. First published September 24, 2009; doi: 10.1152/ajpgi.00237.2009.--Calcium absorption by the intestine is necessary for bone mineralization. Much has been learned about this process and the role of vitamin D metabolites in gene transcription from animal studies, but the molecular mechanisms in humans are less well understood. We have used samples of normal human duodenal mucosa, obtained at endoscopy, to investigate the effects of the vitamin D metabolites, 1[alpha]-dihydroxycholecalciferol [1,25[(OH).sub.2][D.sub.3]] and 25-hydroxycholecalciferol (25OHD), on transcripts on genes involved in calcium absorption and vitamin D metabolism. TRPV6 transcripts were significantly higher after incubation for 6 h with 1,25[(OH).sub.2][D.sub.3] ([10.sup.-9] mol/l) than after control incubations (median difference 3.1-fold, P < 0.001). Unexpectedly, TRPV6 expression was also higher (2.4-fold, P < 0.02) after incubation with 25OHD ([10.sup.-7] mol/l). Transcripts for the calcium-ATPase, PMCA1, were significantly higher with 1,25[(OH).sub.2][D.sub.3]; CYP24 transcripts were reliably detected after incubation with either metabolite, but calbindin-D9k transcripts were unaffected. The response of TRPV6 to 25OHD and the expression of transcripts for CYP27B1, the 25OHD-1[alpha]-hydroxylase, were significantly correlated (r = 0.82, P < 0.02). Basal duodenal expression of TRPV6 and CYP27B1 were significantly associated (r = 0.72, P < 0.001) in a separate previously reported series of subjects. Multiple regression analysis of the associations with basal duodenal TRPV6 expression identified CYP27B1 expression and serum 1,25[(OH).sub.2]D as major factors. Expression of the CYP27B1 protein was demonstrated immunohistochemically in duodenal mucosa. This study has shown that human duodenal TRPV6, PMCA1, and CYP24 transcripts respond rapidly to 1,25[(OH).sub.2][D.sub.3] and provides evidence suggesting that local duodenal production of 1,25[(OH).sub.2][D.sub.3] by 25OHD-1[alpha]-hydroxylase may have a role in human calcium absorption. cholecalciferol; calcium transporter; intestine; organ culture doi: 10.1152/ajpgi.00237.2009