Vitamin D signaling is modulated on multiple levels in health and disease
Vitamin D signaling is modulated on multiple levels in health and disease
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DOI：
10.1016/j.mce.2005.11.039
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发表时间：
2006-03-27
影响因子：
4.1
通讯作者：
Jakob, F
中科院分区：
文献类型：
--
作者：
Ebert, R;Schütze, N;Jakob, F
维生素D信号传导依赖于活性维生素D受体（VDR）配体1.25-二羟基胆钙化醇的可用性和周转率以及VDR反式激活的效率。活化和失活开环甾类代谢p450酶，例如25-羟化酶、1 α-羟化酶和24-羟化酶，负责基于皮肤中的底物产生和前体的营养摄入的配体可用性。活性激素的净利用率取决于底物的递送以及活化酶和失活酶的平衡。1 α-羟化酶是关键的活化酶。它在肾脏中表达用于全身供应，并在靶组织中表达用于局部开环甾类激活。它在肾脏中被低钙摄入和甲状旁腺激素上调，被磷酸酶和促炎信号转导下调。VDR的反式激活依赖于正确的分子结构、有效的核转位以及非配体异源二聚体伴侣类维生素A X受体（RXR）和其他核辅因子的存在。快速维生素D依赖性膜相关效应和连续的第二信使激活发挥自己的基因调控模式。这些效应的膜受体是假设的，但尚未确定。佝偻病是由于维生素D3缺乏引起的维生素D信号传导受损的长期已知的临床综合征。它可能是由遗传缺陷的级联，营养不足，缺乏阳光照射，吸收不良和潜在的疾病，如慢性炎症。在过去的几十年中已经表明，维生素D信号传导的许多修饰剂是遗传性和获得性综合征方面的疾病的靶标，并且维生素D信号传导在多个水平上被调节，并且比单纯的机械配体/受体/DNA相互作用更复杂。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
Vitamin D signaling is dependent on the availability and turnover of the active Vitamin D receptor (VDR) ligand 1.25-dihydroxycholecalciferol and on the efficiency of VDR transactivation. Activating and inactivating secosteroid metabolizing p450 enzymes, e.g. 25-hydroxylases, 1 alpha-hydroxylase and 24-hydroxylase, are responsible for ligand availability on the basis of substrate production in the skin and of nutritional intake of precursors. Net availability of active hormone depends on the delivery of substrate and the balance of activating and inactivating enzymes. 1 alpha-Hydroxylase is the critical activating enzyme. It is expressed in the kidney for systemic supply and in target tissues for local secosteroid activation. It is upregulated in the kidney by low calcium intake and parathyroid hormone, downregulated by phosphatonins and proinflammatory signal transduction. Transactivation of VDR depends on the correct molecule structure, effective nuclear translocation and the presence of the unliganded heterodimer partner retinoid X-receptor (RXR) and other nuclear cofactors. Rapid Vitamin D-dependent membrane associated effects and consecutive second messenger activation exert an own pattern of gene regulation. A membrane receptor for these effects is hypothesized but not yet identified. Rickets is the long known clinical syndrome of impaired Vitamin D signaling due to Vitamin D3 deficiency. It can be caused by inherited defects of the cascade, nutritional deficits, lack of sunlight exposure, malabsorption and underlying diseases like chronic inflammation. It has been shown during the last decades that many modifiers of Vitamin D signaling are targets of disease in terms of inherited and acquired syndromes and that Vitamin D signaling is modulated at multiple levels and is more complex than mere mechanistic ligand/receptor/DNA interaction. (c) 2005 Elsevier Ireland Ltd. All rights reserved.