Máčová L, Bičíková M, Hampl R
Institute of Endocrinology, Prague, Czech Republic.
Physiol Res. 2018 Nov 28;67(Suppl 3):S391-S400. doi: 10.33549/physiolres.934006.
Resistance to vitamin D has been known for decades as vitamin D resistant rickets, caused by mutations of the gene encoding for vitamin D receptor (VDR). Findings of extra-skeletal effects of vitamin D and learning of the molecular mechanisms used by its biologically active metabolite calcitriol revealed other ways leading to its impaired sensitivity. Calcitriol takes advantage of both genomic and non-genomic mechanisms through its binding to vitamin D receptor, located not only in the cell nuclei but also in a perinuclear space. On the genomic level the complex of calcitriol bound to VDR binds to the DNA responsive elements of the controlled gene in concert with another nuclear receptor, retinoid X receptor, and expression of the VDR itself is controlled by its own ligand. These elements were found not only in the promotor region, but are scattered over the gene DNA. The gene expression includes a number of nuclear transcription factors which interact with the responsive elements and with each other and learning how they operate would further contribute to revealing causes of the impaired vitamin D sensitivity. Finally, the examples of major disorders are provided, associated with impairment of the vitamin D function and its receptor.
数十年来，维生素D抵抗一直以维生素D抵抗性佝偻病为人所知，它由编码维生素D受体（VDR）的基因突变引起。维生素D骨骼外作用的发现以及对其生物活性代谢产物骨化三醇所采用分子机制的了解，揭示了导致其敏感性受损的其他途径。骨化三醇通过与维生素D受体结合，利用基因组和非基因组机制，维生素D受体不仅位于细胞核中，也位于核周空间。在基因组水平上，与VDR结合的骨化三醇复合物与另一种核受体视黄酸X受体协同结合到受控基因的DNA反应元件上，VDR自身的表达则由其自身配体控制。这些元件不仅存在于启动子区域，还散布在基因DNA上。基因表达包括许多与反应元件相互作用并彼此相互作用的核转录因子，了解它们的作用方式将进一步有助于揭示维生素D敏感性受损的原因。最后，提供了与维生素D功能及其受体受损相关的主要疾病实例。
