Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis
Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis
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DOI：
10.1182/blood-2003-11-3872
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发表时间：
2004-09-01
期刊：
影响因子：
20.3
通讯作者：
Trinder, D
中科院分区：
文献类型：
--
作者：
Chua, ACG;Olynyk, JK;Trinder, D
遗传性血色素沉着病 (HH) 是一种由 HFE 基因 C282Y 突变引起的铁超载疾病。在 HH 中，血浆非转铁蛋白结合铁 (NTBI) 水平升高，且 NTBI 主要与柠檬酸盐结合。本研究的目的是探讨 NTBI 在 Hfe 敲除小鼠肝铁负荷发病机制中的重要性。与对照小鼠相比，Hfe 敲除小鼠的血浆 NTBI 水平增加了 2.5 倍。与对照小鼠（17.8 +/- 2.7 pmol Fe/mg 蛋白质/分钟；P < .001；平均 SEM；n = 7）相比，从 Hfe 敲除小鼠中分离出的肝细胞对柠檬酸铁的总摄取量（34.1 +/- 2.8 pmol Fe/mg 蛋白质/分钟）增加了 2 倍。亚铁离子螯合剂、红菲咯啉二磺酸盐和2',2-联吡啶抑制两种小鼠肝细胞对柠檬酸铁的摄取。二价金属离子抑制肝细胞对柠檬酸铁的吸收，二铁转铁蛋白也是如此。 Hfe 敲除小鼠的肝细胞中二价金属转运蛋白 1 (DMT1) mRNA 和蛋白质表达增加了约 2 倍。我们得出结论，Hfe 敲除小鼠的肝细胞摄取 NTBI 有助于肝铁负荷。三价铁离子被还原为亚铁离子，并通过与二铁转铁蛋白共享的途径被肝细胞吸收。二价金属对摄取的抑制和 DMT,I 表达的上调表明 NTBI 摄取是由 DMT1 介导的。 (C) 2004 年，美国血液学会。
Hereditary hemochromatosis (HH) is an iron-overload disorder caused by a C282Y mutation in the HFE gene. In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate. The aim of this study was to examine the importance of NTBI in the pathogenesis of hepatic iron loading in Hfe knockout mice. Plasma NTBI levels were increased 2.5-fold in Hfe knockout mice compared with control mice. Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 +/- 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 +/- 2.7 pmol Fe/mg protein/min; P < .001; mean SEM; n = 7). Ferrous ion chelators, bathophenanthroline disulfonate, and 2',2-bipyridine inhibited ferric citrate uptake by hepatocytes from both mouse types. Divalent metal ions inhibited ferric citrate uptake by hepatocytes, as did diferric transferrin. Divalent metal transporter 1 (DMT1) mRNA and protein expression was increased approximately 2-fold by hepatocytes from Hfe knockout mice. We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading. Ferric ion was reduced to ferrous ion and taken up by hepatocytes by a pathway shared with diferric transferrin. Inhibition of uptake by divalent metals and up-regulation of DMT,I expression suggested that NTBI uptake was mediated by DMT1. (C) 2004 by The American Society of Hematology.