维生素D受体最新研究进展

维生素D受体(vitamin D receptor,VDR)是一种核转录因子,通过与配体特异结合,调控多种基因的表达,从而调节多种生命活动的进行.本文总结了近年来VDR的研究进展,主要包括VDR的作用机制、VDR行使功能所需共激活子及共抑制子、VDR在生长分化、免疫调节和抑制肿瘤等方面的作用及VDR配体类似物在药物开发研究领域的最新进展.     

Suppression of PTH by the vitamin D analog eldecalcitol is modulated by its high affinity for the serum vitamin D-binding protein and resistance to metabolism

Eldecalcitol [1α,25‐dihydroxy‐2β‐(3‐hydroxypropyloxy)vitamin D₃], a vitamin D analog with enhanced efficacy for treatment of osteoporosis, has been found to be less potent than 1,25‐dihydroxyvitamin D₃ (calcitriol) in suppressing PTH in vivo. To define the mechanism for the latter observation, we compared the effects of eldecalcitol and calcitriol on PTH secretion by bovine parathyroid cells. While the two compounds showed similar potency when the cells were cultured in medium containing 15% newborn calf serum, eldecalcitol was 100 times more potent than calcitriol in the absence of serum. Eldecalcitol has a higher affinity for the serum vitamin D‐binding protein (DBP), and therefore binding to DBP, and possibly other serum components, appears to limit the uptake and activity of eldecalcitol in parathyroid cells, providing an explanation for the lower PTH suppressing activity in vivo (100% serum). However, the 100‐fold higher activity of eldecalcitol in the absence of serum was unexpected since the VDR affinity for eldecalcitol is eightfold lower than for calcitriol. The enhanced activity was not due to preferential uptake, but to a resistance to metabolism. While 1 nM [³H]calcitriol was completely degraded within 24 h, [³H]eldecalcitol was not metabolized, despite the induction of the vitamin D catabolic enzyme, 24‐hydroxylase (CYP24A). The resistance to metabolism is the likely explanation for the higher potency of eldecalcitol in suppressing PTH in cell culture lacking serum. Thus, the unique properties of eldecalcitol in vivo can be attributed, at least in part, to its high‐DBP affinity which increases the half‐life, but limits the uptake of eldecalcitol, and to its reduced metabolism, which prolongs the activity of this analog in target tissues. J. Cell. Biochem. 112: 1348–1352, 2011. © 2011 Wiley‐Liss, Inc.     

Association of vitamin D receptor BsmI (rs1544410) gene polymorphism with the intact parathyroid hormone (iPTH) level among patients with end-stage renal disease

Abstract

Association of vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism with the intact parathyroid hormone (iPTH) level among patients with end-stage renal disease (ESRD) from the published reports is still conflicting. This meta-analysis was performed to evaluate the relationship between VDR BsmI (rs1544410) gene polymorphism and the iPTH level among patients with ESRD. The association studies were identified from PubMed, and Cochrane Library on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Six reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with iPTH level among patients with ESRD. In this meta-analysis, the iPTH level in ESRD patients carrying BsmI Bb genotype was higher than that in ESRD patients carrying bb genotype in overall populations (Bb versus bb: OR?=?61.40, 95% CI: 19.65–103.16, p?=?0.004). However, the iPTH level in ESRD patients carrying BB genotype was not significant different from that in ESRD patients with Bb genotype and bb genotype in overall populations (BB versus Bb: OR?=??18.30, 95% CI: ?126.28–89.69, p?=?0.74; BB versus bb: OR?=?22.85, 95% CI: ?70.81–116.51, p?=?0.63). Furthermore, the results for Caucasians were similar to those in overall populations. In conclusion, the iPTH level in ESRD patients carrying BsmI Bb genotype was higher than that in ESRD patients carrying bb genotype in overall populations and in Caucasians. However, more studies should be conducted to confirm it.     

Association of the polymorphism of the vitamin D receptor gene (VDR) with the risk of leprosy in the Brazilian Amazon

The transmission and evolution of leprosy depends on several aspects, including immunological and genetic factors of the host, as well as genetic factors of Mycobacterium leprae. The present study evaluated the association of single nucleotide polymorphisms (SNPs) on the FokI (rs2228570), TaqI (rs731236), ApaI (rs7975232) regions of the vitamin D receptor (VDR) gene with leprosy. A total of 405 individuals were evaluated, composed by groups of 100 multibacillary (MB) and 57 paucibacillary (PB) patients, and 248 healthy contacts. Blood samples were collected from patients and contacts. The genotyping was performed by sequencing of the interest regions. The alleles of the studied SNPs, and SNP FokI genotypes, were not associated with leprosy. For the SNP on TaqI region, the relationship between the tt genotype, and for the SNP ApaI, the AA genotype, revealed an association with susceptibility to MB form, while Aa genotype with protection. The extended genotypes AaTT and AaTt of ApaI and TaqI were associated with protection against MB form. Further studies analyzing the expression of the VDR gene and the correlation with its SNPs might help to clarify the role of polymorphisms on the immune response in leprosy.     

IMMUNOCHEMICAL IDENTIFICATION OF THE 1,25-DIHYDROXYVITAMIN D3RECEPTOR PROTEIN IN HUMAN HEART

A number of recent clinical observations suggest that vitamin D₃plays an important role in maintaining normal cardiovascular function, either directly through its receptor in cardiac muscle, or indirectly through its infuence on circulating levels of calcium or on other regulatory factors. By using an antibody directed against the recombinant vitamin D₃receptor, we have identified the receptor protein for 1,25(OH)₂D₃in tissue from two human hearts. The identification of the 1,25(OH)₂D₃receptor in human heart lends credence to the hypothesis that 1,25(OH)₂D₃directly effects the human heart and may be involved in several clinically relevant pathological conditions involving the vitamin D₃endocrine system.     

Immunoreactive parathyroid hormone levels in platyrrhini and catarrhini: A comparative analysis with three different assays

Serum concentrations of the hormonal form of vitamin D₃—1,25-dihydroxy-vitamin D₃ [1,25-(OH)₂-D₃]—are elevated in many genera of platyrrhines when compared to catarrhines; this elevation is presumed to result from a decrease in the ability of the target cell receptor effectively to recognize 1,25-(OH)₂-D₃. The activity of the renal 25-hydroxyvitumin D₃-1α-hydroxylase, the mammalian enzyme which synthesizes the majority of the circulating 1,25-(OH)₂-D₃, is accelerated by parathyroid hormone (PTH). In order to determine whether the elevated serum concentrations of 1,25-(OH)₂-D₃ in platyrrhines were the result of relative hyperparathyroidism, we measured serum levels of immunoreactive parathyroid hormone (iPTH) in normocalcemic platyrrhines, catarrhines, and human subjects with assays that recognize different domains of the human PTH molecule. Antisera directed against the biologically active, aminoterminus of PTH yielded comparable mean values for iPTH among three test groups. The mean concentration of iPTH as assessed by a “proximal” midregion assay was significantly reduced in platyrrhine serum when compared to either human or catarrhine serum. A “distal” midregion assay yielded a reduced mean value for iPTH in both platyrrhine and catarrhine serum when compared to human serum. These data suggest that 1) high circulating levels of 1,25-(OH)₂-D₃ in New World primates are not the result of hyperparathyroidism; and 2) structural homology between human and primate PTH diminishes progressively as one moves toward the carboxyterminus of the molecule and is lost more rapidly in the platyrrhine than in the catarrhine hormone.     

Vitamin D receptor gene polymorphisms (TaqI and ApaI) in relation to 25-hydroxyvitamin D levels and coronary artery disease incidence

Abstract

Context/objective: Previous studies have illustrated the association of the ApaI and TaqI polymorphisms of the vitamin D receptor gene, located in non-coding and coding regions, respectively, with diseases such as cancer and cardiovascular disease; however, investigating such association in Egyptian patients with coronary artery disease (CAD) has never been formerly attempted. Materials and methods: Male patients (n?=?137), 35–50 years of age, with verified CAD, were recruited alongside age- and sex-matched controls (n?=?58). Genotyping and 25-hydroxyvitamin D [25(OH)D] measurement were performed by polymerase chain reaction RFLP and HPLC, respectively. Results: Comparison of the genotypic distribution of both the TaqI and ApaI polymorphisms between patients and controls yielded insignificant results (p?=?0.55 and 0.7, respectively). Comparison of the allelic distribution of both polymorphisms also yielded insignificant results. The TaqI polymorphism was not found to predict 25(OH)D levels, whereas the wild-type genotype of the ApaI polymorphism was associated with greater levels of 25(OH)D (p?=?0.02), taking all subjects into consideration. Discussion/conclusion: This study presents the ApaI and TaqI polymorphisms as non-influencing players in the pathogenesis of CAD in Egyptian males and the ability of only the ApaI polymorphism to predict 25(OH)D levels, thus warranting further investigations of the triangular relationship between the polymorphisms, 25(OH)D and CAD incidence.     

Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice

Vitamin D receptor (VDR) mediates vitamin D signaling involved in bone metabolism, cellular growth and differentiation, cardiovascular function, and bile acid regulation. Mice with an intestine-specific disruption of VDR (Vdr^ΔIEpC) have abnormal body size, colon structure, and imbalance of bile acid metabolism. Lithocholic acid (LCA), a secondary bile acid that activates VDR, is among the most toxic of the bile acids that when overaccumulated in the liver causes hepatotoxicity. Because cytochrome P450 3A4 (CYP3A4) is a target gene of VDR-involved bile acid metabolism, the role of CYP3A4 in VDR biology and bile acid metabolism was investigated. The CYP3A4 gene was inserted into Vdr^ΔIEpC mice to produce the Vdr^ΔIEpC/3A4 line. LCA was administered to control, transgenic-CYP3A4, Vdr^ΔIEpC, and Vdr^ΔIEpC/3A4 mice, and hepatic toxicity and bile acid levels in the liver, intestine, bile, and urine were measured. VDR deficiency in the intestine of the Vdr^ΔIEpC mice exacerbates LCA-induced hepatotoxicity manifested by increased necrosis and inflammation, due in part to over-accumulation of hepatic bile acids including taurocholic acid and taurodeoxycholic acid. Intestinal expression of CYP3A4 in the Vdr^ΔIEpC/3A4 mouse line reduces LCA-induced hepatotoxicity through elevation of LCA metabolism and detoxification, and suppression of bile acid transporter expression in the small intestine. This study reveals that intestinal CYP3A4 protects against LCA hepatotoxicity.     

Expression patterns of vitamin D receptor in human prostate

UV exposure and serum levels of vitamin D have been linked in several studies with prostate cancer risk. At the cellular level, the principal action of vitamin D is mediated though vitamin D receptors (VDR). Since prostate cancer is a disease strongly associated with age, we examined the presence of VDR in normal prostate from donors of various ages to determine if the VDR expression pattern changed with age. We also compared the VDR expression in the peripheral and central zones of the prostate to determine if the expression pattern varied by location. Immunohistochemical studies were performed on paraffin-embedded tissue from cases selected by the following age decades; 10-19, 20-29, 30-39, 40-49, 50-59, and 60-69. Both the central and peripheral zones were examined for VDR expression. The intensity of VDR expression in prostate was compared with expression in different types of human tissues. Mean VDR expression was lowest in the 10-19 years of age group. The intensity of the nuclear VDR was higher though the fifth decade, and then declined in cases of ages 60-70. When multiple sections of the same donor prostate were compared, VDR expression was greater in the peripheral zone compared to the central zone.