Title： New aspects of vitamin D metabolism and action — addressing the skin as source and target

1 Mutation in the enzymes involved in vitamin D metabolism cause human diseases such as rickets.
参与维生素D代谢酶的突变会导致一些人类疾病，比如佝偻病。

2 Vitamin D binding protein is the major transport protein for vitamin D metabolites, but with the exception of a few tissues such as the kidney, it is the free forms of these metabolites that enter cells.
维生素D结合蛋白是维生素D代谢产物的主要转运蛋白，但是除了一些组织（例如肾脏）外，这些代谢产物的游离形式进入细胞。（也就是说，除了肾脏以外，其余组织中VD的代谢产物都很少）

3 The vitamin D receptor (VDR) is the major mediator of vitamin D biological action

4 皮肤是研究维生素D的极好的非骨骼模型，因为它是维生素D的来源，含有维生素D代谢酶并表达VDR，使其也成为靶组织。

5 Knockout of Cyp2r1 in mice results in a reduction in blood levels of 25OHD by >50%, but not to zero. Moreover, mutations in CYP2R1 in humans leads to rickets.(cyp21r1不是合成25（OH）的唯一酶，但是是主要的）

6 inactivating mutations in CYP24A1 are one cause of idiopathic infantile hypercalcaemia (IIH) in children and recurrent kidney stone formation in adults（cyp24A1失活使成人发生肾结石，儿童高钙血症）

7 Vitamin D binding protein (DBP), which binds
to ~85% of the circulating 25OHD and 1,25(OH)2D,
is primarily responsible for such transport.
(与DBP结合的维生素D很多也会发挥功能的单位，但是游离状态的就较少，发挥功能就比较微弱）

8 From the mitochondria, HSP70 is then thought to transport 1,25(OH)2D into the nucleus where it binds to the vitamin D receptor (VDR)

热休克蛋白(heatshockproteins，HSPs)又称应激蛋白(stressprotein，sp)，是生物体细胞在热诱导下合成的一组具有高度保守性的蛋白质。HSPs被发现与恶性肿瘤的发生、发展、复发及预后关系密切。

在所研究的细胞中，HSP70已被确定为25OHD的潜在转运体，通过质膜到线粒体，在那里它被转化为1,25(OH)2D23。从线粒体中，HSP70被认为可以将1,25(OH)2D运输到细胞核中，在那里它与维生素D受体(VDR)23结合。HSP70对25OHD的亲和力比DBP高，DBP能使25OHD通过细胞膜运输，但对1,25(OH)2D的亲和力比VDR低，VDR能使1,25(OH)2D在细胞核中卸载到VDR上。

9 CYP24A1和CYP3A4都具有24-羟化酶和23-羟化酶活性，尽管至少对于CYP24A1而言，该比例是物种特异性的，而在人中24-羟化酶活性占主导，而相反，在鼠中（ opossum）23-羟化酶则占优势。

10 1,24,25(OH)3D has substantial affinity for the VDR with biological activity being ~10% that of 1,25(OH)2D.

11 However, it is important to note that patients with vitamin D deficiency present with low 25OHD levels and often normal 1,25(OH)2D levels, except those with extreme vitamin D deficiency.

12 维生素D受体（VDR）-类维生素X受体（RXR）异二聚体采用不同的构象，具体取决于DNA反应元件中的序列，配体结构和共调控蛋白结合。

13 Genome-wide studies have noted that actions of 1,25(OH)2D involve regulation of gene activity at a range of locations. VDR binding may be many kilobases upstream or downstream of regulated genes.

文献title：The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights

1 Although this wider distribution is not in dispute, the concept that the VDR is ubiquitously distributed has been highly overstated. Indeed, the VDR is often expressed in one or more cellular subsets that frequently represent only minor components of more complex organs. Thus, there has been difficulty in detecting the VDR in tissues such as muscle liver , and particularly the CNS , where the incredible sensitivity of quantitative reverse transcriptase PCR analysis provides evidence of low levels of VDR RNA transcripts that are then difficult to confirm at the protein level using much less sensitive, antibody-based detection methods.

VDR的这种广泛的分配没有争议，但是VDR无处不在的分配概念已经被高估了。 实际上，VDR通常在一个或多个细胞亚群中表达，而这些亚群通常仅代表更复杂器官的次要成分。 因此，难以检测组织（例如肌肉，肝脏，尤其是中枢神经系统）中的VDR，其中定量逆转录酶PCR分析令人难以置信的敏感性提供了低水平VDR RNA的证据 然后，使用灵敏度较低，基于抗体的检测方法很难在蛋白质水平上确认转录本。