Determinants of circulating 1,25-dihydroxyvitamin D3 levels:: the role of renal synthesis and catabolism of vitamin D
Determinants of circulating 1,25-dihydroxyvitamin D3 levels:: the role of renal synthesis and catabolism of vitamin D
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DOI：
10.1016/j.jsbmb.2004.03.089
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发表时间：
2004-05-01
影响因子：
4.1
通讯作者：
Morris, HA
中科院分区：
文献类型：
--
作者：
Anderson, PH;O'Loughlin, PD;Morris, HA
决定第二类固醇1,25-二羟基维生素D-3 （1,25 d）水平的分子机制细节仍有待阐明。目前控制血清1,25 d水平的范式是通过许多生理因素严格调节肾脏25-羟基维生素d -1 α -羟化酶（CYP27B1）活性。1,25 d的产生也受细胞色素P450酶25-羟基维生素d -24-羟化酶（CYP24）的调节，该酶通过侧链羟基化反应使1,25 d失活。我们最近证明，肾脏CYP27B1和CYP24的表达同样有助于调节血清1,25 d水平。我们现在描述肾脏维生素D受体（VDR）表达在确定血清1,25D水平中的贡献。随着饲粮钙摄入量的增加，血清1,25 d水平降低。我们测量了不同钙含量（0.05 ~ 1%）的动物肾脏RNA提取物中CYP27B1、CYP24和VDR的mRNA水平。血清1,25 d水平与肾脏CYP24 mRNA水平呈负相关（R-2 = 0.35, P < 0.01），而肾脏VDR与肾脏CYP24 mRNA水平呈正相关（R-2 = 0.80, P < 0.001）。然而，当纳入多元线性回归分析时，只有肾脏VDR mRNA仍然是肾脏CYP24表达的重要决定因素（多重R-2 = 0.89, P < 0.001）。这些发现表明，肾脏CYP24活性与肾脏CYP27B I协同作用，控制血清1,25 d水平，血清1,25 d通过肾脏VDR刺激肾脏CYP24表达。(C) 2004 Elsevier Ltd.版权所有。
Details of the molecular mechanisms determining levels of the secosteroid, 1,25-dihydroxyvitamin D-3 (1,25D) remain to be elucidated. kThe current paradigm for the control of serum 1,25D levels is the tight regulation of renal 25-hydroxyvitamin D-1alpha-hydroxlase (CYP27B1) activity by a number of physiological factors. 1,25D production is also regulated by the cytochrome P450 enzyme, 25-hydroxyvitamin D-24-hydroxylase (CYP24),,which through side chain hydroxylation reactions, inactivates 1,25D. We have recently demonstrated that renal CYP27B1 and CYP24 expression contribute equally to regulating serum 1,25D levels. We now describe the contribution of renal Vitamin D receptor (VDR) expression in determining serum 1,25D levels. Serum 1,25D levels were decreased when the dietary calcium intake was increased. We measured mRNA levels for CYP27B1, CYP24 and VDR in kidney RNA extracts from animals fed diets containing different levels of calcium, ranging from 0.05 to I %. Serum 1,25D levels were negatively correlated with renal CYP24 mRNA levels (R-2 = 0.35, P < 0.01) while renal VDR is positively correlated with renal CYP24 mRNA (R-2 = 0.80, P < 0.001). However, only renal VDR mRNA remained a significant determinant of renal CYP24 expression when both these variables were included in multiple linear regression analysis (multiple R-2 = 0.89, P < 0.001). These findings suggest that kidney CYP24 activity acts in concert with kidney CYP27B I to control serum 1,25D levels and that serum 1,25D stimulates renal CYP24 expression by acting through the renal VDR. (C) 2004 Elsevier Ltd. All rights reserved.