Molecular Mechanisms of Vitamin D Action
Molecular Mechanisms of Vitamin D Action
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DOI：
10.1007/s00223-012-9619-0
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发表时间：
2013-02-01
影响因子：
4.2
通讯作者：
Jurutka, Peter W.
中科院分区：
文献类型：
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作者：
Haussler, Mark R.;Whitfield, G. Kerr;Jurutka, Peter W.
维生素D的激素代谢物1 α，25-二羟基维生素D-3（1，25 D）通过与维生素D受体（VDR）结合引发生物反应。当被1，25 D占据时，VDR与类维生素A X受体（RXR）相互作用，形成异二聚体，与1，25 D直接控制的基因区域中的维生素D反应元件结合。通过募集辅激活因子或辅抑制因子的复合物，配体激活的VDR-RXR调节编码蛋白质的基因的转录，这些蛋白质传播维生素D的传统功能，包括发出肠道钙和磷酸盐吸收信号以影响骨骼和钙稳态。因此，维生素D在特定细胞中的作用取决于足够浓度的1，25 D配体的代谢产生或递送、足够的VDR和RXR辅助受体蛋白的表达以及转录应答的细胞特异性编程以调节编码在介导维生素D的作用中起作用的蛋白质的选择基因。例如，1，25 D诱导RANKL、SPP 1（骨桥蛋白）和BGP（骨钙素）来控制骨矿物质重塑; TRPV 6、CaBP 9 k和claudin 2来促进肠钙吸收; TRPV 5、klotho和Npt 2c来调节肾钙和磷酸盐重吸收。VDR似乎在角质形成细胞中通过1，25 D解除配体而发挥作用，以通过调节基因如CASP 14、S100 A8、SOSTDC 1和影响Wnt信号传导的其他基因来驱动哺乳动物毛发周期。最后，可选择的低亲和力非维生素D VDR配体，例如，石胆酸、二十二碳六烯酸和姜黄素。组合的替代VDR配体和基因表达的1，25 D/VDR控制可以延缓慢性衰老疾病，如骨质疏松症、2型糖尿病、心血管疾病和癌症。
The hormonal metabolite of vitamin D, 1 alpha,25-dihydroxyvitamin D-3 (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP9k, and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer.