Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis
Transferrin receptor 2: Continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis
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DOI：
10.1073/pnas.040548097
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发表时间：
2000-02-29
影响因子：
11.1
通讯作者：
Sly, WS
中科院分区：
文献类型：
--
作者：
Fleming, RE;Migas, MC;Sly, WS
遗传性血色素沉着病 (HH) 是一种常见的常染色体隐性遗传疾病，其特征是膳食铁的过量吸收和多个组织（特别是肝脏）中进行性铁沉积。铁中毒引起的肝病是 HH 死亡的主要原因。尽管经典转铁蛋白受体 (TfR) 下调，HH 中的肝铁负荷仍呈渐进性。最近，一种与 TfR 高度同源的人类 cDNA 被鉴定并报道编码一种与全转铁蛋白结合并介导转铁蛋白结合铁的摄取的蛋白质 (TfR2)。我们独立鉴定了编码人类 TfR2 的小鼠直系同源物的全长小鼠 EST。尽管 TfR2 转录本在编码区与鼠 TfR 同源，但不包含 TfR mRNA 3' 非翻译序列中发现的铁反应元件。为了确定 TfR2 在肝脏铁吸收中的潜在作用，我们研究了正常小鼠和膳食铁超载（2% 羰基铁）、膳食铁缺乏（胃壁细胞消融）和 HH (HFE -/-) 小鼠模型中 TfR 和 TfR2 的表达。 Northern印迹分析表明TfR和TfR2具有不同的组织特异性表达模式，其中TfR2仅在TfR表达较低的肝脏中高度表达。原位杂交证明肝细胞中有丰富的 TfR2 表达。与 TfR 相比，缺铁时肝脏中 TfR2 的表达并未增加。此外，TfR2 的肝脏表达不会因膳食铁负荷或 HH 的 HFE -/- 模型而下调。根据这些观察结果，我们提出，即使 TfR 因铁过载而下调，TfR2 仍允许肝细胞持续摄取 Tf 结合铁，并且这种摄取有助于 HH 中肝脏对铁负荷的敏感性。
Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite downregulation of the classical transferrin receptor (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-length murine EST encoding the mouse orthologue of the human TfR2. Although homologous to murine TfR in the coding region, the TfR2 transcript does not contain the iron-responsive elements found in the 3' untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models of dietary iron overload (2% carbonyl iron), dietary iron deficiency (gastric parietal cell ablation), and HH (HFE -/-). Northern blot analyses demonstrated distinct tissue-specific patterns of expression for TfR and TfR2, with TfR2 expressed highly only in liver where TfR expression is low. In situ hybridization demonstrated abundant TfR2 expression in hepatocytes. In contrast to TfR, TfR2 expression in liver was not increased in iron deficiency. Furthermore, hepatic expression of TfR2 was not downregulated with dietary iron loading or in the HFE -/- model of HH. From these observations, we propose that TfR2 allows continued uptake of Tf-bound iron by hepatocytes even after TfR has been down-regulated by iron overload, and this uptake contributes to the susceptibility of liver to iron loading in HH.