Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein
Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein
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DOI：
10.1172/jci5244
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发表时间：
1999-01-01
影响因子：
15.9
通讯作者：
Cooke, NE
中科院分区：
文献类型：
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作者：
Safadi, FF;Thornton, P;Cooke, NE
采用靶向诱变方法制备维生素D结合蛋白（DBP）缺乏小鼠，建立DBP在维生素D代谢和作用中的生物学功能模型。在富含维生素D的饮食中，DBP-/-小鼠的血清总维生素D代谢物水平较低，但其他方面正常。当短时间维持维生素D缺乏饮食时，DBP-/-，而不是DBP+/+，小鼠出现继发性甲状旁腺功能亢进，并伴有与维生素D缺乏相关的骨骼变化。DBP可显著延长25(OH)D的血清半衰期，而维生素D的半衰期延长不明显，其原因是DBP可减缓维生素D在肝脏中的吸收，并提高其在肝脏中转化为25(OH)D的效率。过量摄入维生素D后，DBP-/-小鼠对高钙血症及其毒性作用的易感程度出乎意料地降低。1,25(OH)(2)D在DBP-/-小鼠中更快地诱导维生素D依赖性钙结合蛋白-D- 9k基因的峰值稳态mRNA水平。因此，舒张压的作用是维持维生素D代谢物的稳定血清储存，并调节其生物利用度、活化率和终末器官反应性。这些特性可能是为了在维生素D可用性变化的环境中稳定和维持血清维生素D水平而进化的。
A line of mice deficient in vitamin D binding protein (DBP) was generated by targeted mutagenesis to establish a model for analysis of DBP's biological functions in vitamin D metabolism and action. On vitamin D-replete diets, DBP-/- mice had low levels of total serum vitamin D metabolites but were otherwise normal. When maintained on vitamin D-deficient diets for a brief period, the DBP-/-, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency. DBP markedly prolonged the serum half-life of 25(OH)D and less dramatically prolonged the half-life of vitamin D by slowing its hepatic uptake and increasing the efficiency of its conversion to 25(OH)D in the liver. After an overload of vitamin D, DBP-/- mice were unexpectedly less susceptible to hypercalcemia and its toxic effects. Peak steady-state mRNA levels of the vitamin D-dependent calbindin-D-9K gene were induced by 1,25(OH)(2)D more rapidly in the DBP-/- mice. Thus, the role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailability, activation, and end-organ responsiveness. These properties may have evolved to stabilize and maintain serum levels of vitamin D in environments with variable vitamin D availability.