Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency
Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency
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DOI：
10.1093/jn/136.5.1236
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发表时间：
2006-05-01
影响因子：
4.2
通讯作者：
Vulpe, CD
中科院分区：
文献类型：
--
作者：
Chen, HJ;Huang, G;Vulpe, CD
在哺乳动物中，铜和铁的代谢是相交的。铜缺乏同时导致某些组织中铁水平下降和缺铁性贫血，而在其他组织中则会导致铁超载，如肠道和肝脏。多铜铁氧化物酶、肝素和铜蓝蛋白对铜的需求可能解释了哺乳动物体内铜和铁稳态之间的这种联系。我们研究了体内和体外铜缺乏对Hephestn(Heph)表达和活性的影响。分娩当天将C57BL/6J小鼠随机分为2组。其中一组喂以缺铜饲料，另一组喂以对照饲料6wk。铜缺乏的小鼠的肝磷脂和铜蓝蛋白(与对照组的50%相似)铁氧合酶活性显著降低。与对照组相比，缺铜组小鼠肝脏组织中的海普西丁表达显著下调(与对照组的60%相似)，肠细胞中铁蛋白1的mRNA和蛋白水平分别增加到对照组的2.5倍和10倍，提示缺铜小鼠存在全身性缺铁。有趣的是，Hephestn蛋白水平显著降低，接近对照组的40%，这表明肠细胞铜含量的减少会导致Hephestn合成和/或稳定性的降低。我们还在体外检测了铜缺乏对HT29细胞株中Hephestn的影响，发现Hephestn的合成和活性显著降低。体内和体外研究都表明，铜是肝磷脂正确加工和/或稳定所必需的。
Copper and iron metabolism intersect in mammals. Copper deficiency simultaneously leads to decreased iron levels in some tissues and iron deficiency anemia, whereas it results in iron overload in other tissues such as the intestine and liver. The copper requirement of the multicopper ferroxidases hephaestin and ceruloplasmin likely explains this link between copper and iron homeostasis in mammals. We investigated the effect of in vivo and in vitro copper deficiency on hephaestin (Heph) expression and activity. C57BL/6J mice were separated into 2 groups on the day of parturition. One group was fed a copper-deficient diet and another was fed a control diet for 6 wk. Copper-deficient mice had significantly lower hephaestin and ceruloplasmin (similar to 50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (similar to 60% of controls), and enterocyte mRNA and protein levels of ferroportin1 were increased to 2.5 and 10 times, respectively, relative to controls, by copper deficiency, indicating a systemic iron deficiency in the copper-deficient mice. Interestingly, hephaestin protein levels were significantly decreased to similar to 40% of control, suggesting that decreased enterocyte copper content leads to decreased hephaestin synthesis and/or stability. We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity. Both in vivo and in vitro studies indicate that copper is required for the proper processing and/or stability of hephaestin.