Chen Huijun, Huang Gang, Su Trent, Gao Hua, Attieh Zouhair K, McKie Andrew T, Anderson Gregory J, Vulpe Chris D
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720-3104, USA.
J Nutr. 2006 May;136(5):1236-41. doi: 10.1093/jn/136.5.1236.
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 (approximately 50% of controls) ferroxidase activity. Liver hepcidin expression was significantly downregulated by copper deficiency (approximately 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 approximately 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.
在哺乳动物中，铜和铁的代谢相互关联。铜缺乏会同时导致某些组织中铁水平降低以及缺铁性贫血，而在其他组织如肠道和肝脏中则会导致铁过载。多铜铁氧化酶血浆铜蓝蛋白和铁转运蛋白可能需要铜来维持其活性，这或许可以解释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铁转运蛋白表达和活性的影响。在分娩当天，将C57BL/6J小鼠分为两组。一组喂食缺铜饮食，另一组喂食对照饮食，持续6周。缺铜小鼠的铁转运蛋白和血浆铜蓝蛋白（约为对照组的50%）铁氧化酶活性显著降低。铜缺乏显著下调了肝脏铁调素的表达（约为对照组的60%），相对于对照组，缺铜使肠上皮细胞中金属离子转运蛋白1的mRNA和蛋白质水平分别增加到2.5倍和10倍，这表明缺铜小鼠存在全身性缺铁。有趣的是，铁转运蛋白的蛋白质水平显著降低至对照组的约40%，这表明肠上皮细胞铜含量降低会导致铁转运蛋白合成和/或稳定性下降。我们还在HT29细胞系中研究了体外铜缺乏对铁转运蛋白的影响，发现铁转运蛋白的合成和活性显著降低。体内和体外研究均表明，铜是铁转运蛋白正常加工和/或稳定性所必需的。
