Liuzzi Juan P, Aydemir Fikret, Nam Hyeyoung, Knutson Mitchell D, Cousins Robert J
Nutritional Genomics Laboratory, Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA.
Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13612-7. doi: 10.1073/pnas.0606424103. Epub 2006 Sep 1.
Zip14 is a member of the SLC39A zinc transporter family, which is involved in zinc uptake by cells. Up-regulation of Zip14 by IL-6 appears to contribute to the hepatic zinc accumulation and hypozincemia of inflammation. At least three members of the SLC39A family transport other trace elements, such as iron and manganese, in addition to zinc. We analyzed the capability of Zip14 to mediate non-transferrin-bound iron (NTBI) uptake by overexpressing mouse Zip14 in HEK 293H cells and Sf9 insect cells. Zip14 was found to localize to the plasma membrane, and its overexpression increased the uptake of both (65)Zn and (59)Fe. Addition of bathophenanthroline sulfonate, a cell-impermeant ferrous iron chelator, inhibited Zip14-mediated iron uptake from ferric citrate, suggesting that iron is taken up by HEK cells as Fe(2+). Iron uptake by HEK and Sf9 cells expressing Zip14 was inhibited by zinc. Suppression of endogenous Zip14 expression by using Zip14 siRNA reduced the uptake of both iron and zinc by AML12 mouse hepatocytes. Zip14 siRNA treatment also decreased metallothionein mRNA levels, suggesting that compensatory mechanisms were not sufficient to restore intracellular zinc. Collectively, these results indicate that Zip14 can mediate the uptake of zinc and NTBI into cells and that it may play a role in zinc and iron metabolism in hepatocytes, where this transporter is abundantly expressed. Because NTBI is commonly found in plasma of patients with hemochromatosis and transfusional iron overload, Zip14-mediated NTBI uptake may contribute to the hepatic iron loading that characterizes these diseases.
Zip14是SLC39A锌转运蛋白家族的成员之一，该家族参与细胞对锌的摄取。白细胞介素-6对Zip14的上调似乎导致了肝脏锌蓄积和炎症性低锌血症。SLC39A家族中至少有三个成员除了转运锌之外，还转运其他微量元素，如铁和锰。我们通过在HEK 293H细胞和Sf9昆虫细胞中过表达小鼠Zip14，分析了Zip14介导非转铁蛋白结合铁（NTBI）摄取的能力。发现Zip14定位于质膜，其过表达增加了（65）Zn和（59）Fe的摄取。加入细胞不透性亚铁螯合剂bathophenanthroline sulfonate可抑制Zip14介导的从柠檬酸铁摄取铁，这表明HEK细胞摄取的铁为Fe(2+)。表达Zip14的HEK和Sf9细胞摄取铁受到锌的抑制。使用Zip14 siRNA抑制内源性Zip14表达可降低AML12小鼠肝细胞对铁和锌的摄取。Zip14 siRNA处理还降低了金属硫蛋白mRNA水平，这表明补偿机制不足以恢复细胞内锌水平。总体而言，这些结果表明Zip14可以介导锌和NTBI进入细胞，并且它可能在该转运蛋白大量表达的肝细胞的锌和铁代谢中发挥作用。由于NTBI常见于血色素沉着症和输血性铁过载患者的血浆中，Zip14介导的NTBI摄取可能导致这些疾病所特有的肝脏铁负荷增加。
