Vitamin D metabolism

Photochemical synthesis of vitamin D3 (cholecalciferol, D3) occurs cutaneously where pro-vitamin D3 (7-dehydrocholesterol) is converted to pre-vitamin D3 (pre-D3) in response to ultraviolet B (sunlight) exposure. DHCR7 encodes the enzyme 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, thereby removing the substrate from the synthetic pathway of vitamin D3, a precursor of 25-hydroxyvitamin D3.The finding that common variants at DHCR7 are strongly associated with circulating 25-hydroxyvitamin D concentrations suggests that this enzyme could have a larger role in regulation of vitamin D status than has previously been recognised. Vitamin D3, obtained from the isomerization of pre-vitamin D3 in the epidermal basal layers or intestinal absorption of natural and fortified foods and supplements, binds to vitamin D-binding protein (DBP) in the bloodstream, and is transported to the liver. D3 is hydroxylated by liver 25-hydroxylases (25-OHase). The resultant 25-hydroxycholecalciferol (25(OH)D3) is 1-hydroxylated in the kidney by 25-hydroxyvitamin D3-1 -hydroxylase (1-OHase). This yields the active secosteroid 1 ,25(OH)2D3 (calcitriol), which has different effects on various target tissues. The synthesis of 1,25(OH)2D3 from 25(OH)D3 is stimulated by parathyroid hormone (PTH) and suppressed by Ca2+, Pi and 1,25(OH)2D3 itself. The rate-limiting step in catabolism is the degradation of 25(OH)D3 and 1,25(OH)2D3 to 24,25(OH)D3 and 1,24,25(OH)2D3, respectively,which occurs through 24-hydroxylation by 25-hydroxyvitamin D 24-hydroxylase (24-OHase), encoded by the CYP24A1 gene. 24,25(OH)D3 and 1,24,25(OH)2D3 are consequently excreted. Vitamin D activity is mediated through binding of 1,25(OH)2D3 to the vitamin D receptor (VDR), which can regulate transcription of other genes involved in cell regulation, growth, and immunity. VDR modulates the expression of genes by forming a heterodimer complex with retinoid-X-receptors (RXR).

维生素D3（胆钙化醇，D3）的photochemical合成过程主要发生在皮肤表层，其中前维生素D3（7-脱氢胆固醇）在紫外线B（阳光）照射下转化为前维生素D3（pre-D3）。DHCR7基因编码的7-脱氢胆固醇还原酶将7-脱氢胆固醇转化为胆固醇，从而移除维生素D3合成途径中的底物，维生素D3是25-羟基维生素D3的前体。研究发现在DHCR7基因中常见的变异与循环中25-羟基维生素D3浓度显著相关，这表明该酶在维生素D状态的调节中可能扮演比以往认识更为重要的角色。维生素D3通过表皮基底层中前维生素D3的同分异构化或通过自然和强化食品及补充剂的肠道吸收获得，在血液中与维生素D结合蛋白（DBP）结合，并被运输至肝脏。肝脏中的25-羟基化酶（25-OHase）对D3进行羟基化。生成的25-羟基胆钙化醇（25(OH)D3）在肾脏中被25-羟基维生素D3-1-羟基化酶（1-OHase）进一步羟基化，从而产生具有不同靶组织效应的活性次甾体1,25(OH)2D3（钙三醇）。25(OH)D3向1,25(OH)2D3的合成受到甲状旁腺激素（PTH）的刺激和钙离子（Ca2+）、磷酸盐（Pi）以及1,25(OH)2D3本身的抑制。代谢过程中的限速步骤是25(OH)D3和1,25(OH)2D3分别降解为24,25(OH)D3和1,24,25(OH)2D3，这一过程通过25-羟基维生素D 24-羟基化酶（24-OHase，由CYP24A1基因编码）的24-羟基化作用实现。24,25(OH)D3和1,24,25(OH)2D3随后被排出体外。维生素D的活性通过1,25(OH)2D3与维生素D受体（VDR）的结合介导，VDR可以调节参与细胞调节、生长和免疫的其他基因的转录。VDR通过与视黄醇X受体（RXR）形成异源二聚体复合物来调节基因的表达。