Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux
Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux
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DOI：
10.1073/pnas.96.19.10812
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发表时间：
1999-09-14
影响因子：
11.1
通讯作者：
Gitlin, JD
中科院分区：
文献类型：
--
作者：
Harris, ZL;Durley, AP;Gitlin, JD
铜蓝蛋白血症是一种常染色体隐性铁代谢障碍，患者可见铁在组织实质内积聚，并伴有血清铜蓝蛋白缺失。对这类患者的遗传学研究揭示了铜蓝蛋白基因的遗传突变。为了阐明铜蓝蛋白在铁稳态中的作用，我们通过干扰小鼠铜蓝蛋白(CP)基因建立了一种无球蛋白血症的动物模型。虽然CP-/-小鼠在出生时是正常的，但它们表现出铁的逐渐积累，以至于到一岁时，所有动物的血清铁蛋白都显著升高，肝脏和脾的铁含量增加了3到Q倍。对这些小鼠受影响组织的组织学分析显示，网状内皮细胞和肝细胞内储存了丰富的铁，CP+/+和CP-/-小鼠的铁动力学研究表明，铁的吸收和血浆铁的周转速度相同，这表明铁的积累是铁周期内分区改变的结果。与这一概念一致，CP-/-小鼠在细胞铁摄取方面没有表现出异常，但在网状内皮细胞和肝细胞外的铁移动方面出现了显著的障碍。我们的发现揭示了铜蓝蛋白在确定具有可动员铁库的细胞的铁外流速率方面的重要生理作用。
Aceruloplasminemia is an autosomal recessive disorder of iron metabolism, Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of aceruloplasminemia by disrupting the murine ceruloplasmin (Cp) gene. Although normal at birth, Cp-/- mice demonstrate progressive accumulation of iron such that by one year of age all animals have a prominent elevation in serum ferritin and a 3- to Q-fold increase in the iron content of the liver and spleen. Histological analysis of affected tissues in these mice shows abundant iron stores within reticuloendothelial cells and hepatocytes, Ferrokinetic studies in Cp+/+ and Cp-/- mice reveal equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp-/- mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.