The role of Hfe in transferrin-bound iron uptake by hepatocytes
The role of Hfe in transferrin-bound iron uptake by hepatocytes
复制标题
DOI：
10.1002/hep.22180
复制
发表时间：
2008-05-01
期刊：
影响因子：
13.5
通讯作者：
Trinder, Debbie
中科院分区：
文献类型：
--
作者：
Chua, Anita C. G.;Herbison, Carly E.;Trinder, Debbie
HFE 相关的遗传性血色素沉着症会导致肝铁超负荷。肝细胞通过转铁蛋白受体 (Tfr) 1 和 Tfr1 独立途径（可能由 Tfr2 介导）获得转铁蛋白结合铁。在本研究中，使用 Hfe 敲除小鼠研究了 We 在通过这些途径调节肝转铁蛋白结合铁吸收中的作用。与 50 nM I-125-Tf-Fe-59（Tfr1 途径）和 5 mu M I-125-Tf-Fe-59（Tfr1 独立或假定的 Tfr2 途径）孵育后，测量 Hfe 敲除、非铁负载和铁负载野生型小鼠的肝细胞对铁和转铁蛋白的吸收。分别通过实时聚合酶链反应和蛋白质印迹法测量 Tfr1 和 Tfr2 信使 RNA (mRNA) 和蛋白质表达。与铁水平和 Tfr1 表达相似的载铁野生型肝细胞相比，Hfe 敲除肝细胞对 Tfr1 介导的铁和转铁蛋白的摄取增加了 40% 至 70%。 Tfr1 独立途径对铁和转铁蛋白的吸收大约是 Tfr1 途径的 100 倍，并且不受 Hfe 缺失的影响。二铁转铁蛋白增加了肝细胞Tfr2蛋白的表达，导致转铁蛋白小幅增加，但不通过Tfr1独立途径吸收铁。结论：肝细胞中Tfr1介导的铁摄取受We调控。 Tfr1 独立途径表现出比 Tfr1 途径大得多的铁吸收能力，但它不受 We 调节。双铁转铁蛋白上调肝细胞 Tfr2 蛋白表达，但不上调铁摄取，表明 Tfr2 在 Tfr1 独立途径中的作用可能有限。
HFE-related hereditary hemochromatosis results in hepatic iron overload. Hepatocytes acquire transferrin-bound iron via transferrin receptor (Tfr) 1 and Tfr1-independent pathways (possibly Tfr2-mediated). In this study, the role of We in the regulation of hepatic transferrin-bound iron uptake by these pathways was investigated using Hfe knockout mice. Iron and transferrin uptake by hepatocytes from Hfe knockout, non-iron-loaded and iron-loaded wild-type mice were measured after incubation with 50 nM I-125-Tf-Fe-59 (Tfr1 pathway) and 5 mu M I-125-Tf-Fe-59 (Tfr1-independent or putative Tfr2 pathway). Tfr1 and Tfr2 messenger RNA (mRNA) and protein expression were measured by real-time polymerase chain reaction and western blotting, respectively. Tfr1-mediated iron and transferrin uptake by Hfe knockout hepatocytes were increased by 40% to 70% compared with iron-loaded wild-type hepatocytes with similar iron levels and Tfr1 expression. Iron and transferrin uptake by the Tfr1-independent pathway was approximately 100-fold greater than by the Tfr1 pathway and was not affected by the absence of Hfe. Diferric transferrin increased hepatocyte Tfr2 protein expression, resulting in a small increase in transferrin but not iron uptake by the Tfr1-independent pathway. Conclusion: Tfr1-mediated iron uptake is regulated by We in hepatocytes. The Tfr1-independent pathway exhibited a much greater capacity for iron uptake than the Tfr1 pathway but it was not regulated by We. Diferric transferrin up-regulated hepatocyte Tfr2 protein expression but not iron uptake, suggesting that Tfr2 may have a limited role in the Tfr1-independent pathway.