Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis
Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis
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DOI：
10.1182/blood-2004-04-1416
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发表时间：
2005-01-01
期刊：
影响因子：
20.3
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
--
作者：
Kawabata, H;Fleming, RE;Koeffler, HP
转铁蛋白受体2（TfR 2）是介导细胞从全转铁蛋白摄取铁的膜糖蛋白。该基因的纯合突变导致人类遗传性血色病的一种形式。我们最近报道了与人类TfR 2（Y250 X）突变相对应的纯合TfR 2（Y245 X）突变小鼠，表现出与遗传性血色病相似的表型。在这项研究中，我们进一步分析了表型以及铁相关基因的表达在这些小鼠通过比较TfR 2突变体和野生型同胞。北方印迹分析表明，铁调素mRNA在肝脏中的表达水平普遍较低，而十二指肠DMT 1，摄取膳食铁的主要转运蛋白，在TfR 2突变小鼠中的表达水平高于野生型同胞。铁调素mRNA在TfR 2突变小鼠中的表达即使在腹膜内铁负荷后仍然很低。在野生型和TfR 2突变小鼠的分离肝细胞中，白细胞介素-6和脂多糖各自诱导hepcidin mRNA的表达。这些结果表明，上调hepcidin表达的炎症刺激是独立的TfR 2和TfR 2是上游的hepcidin的调节途径中的身体铁稳态。(C)2005年美国血液学会。
Transferrin receptor 2 (TfR2) is a membrane glycoprotein that mediates cellular iron uptake from holotransferrin. Homozygous mutations of this gene cause one form of hereditary hemochromatosis in humans. We recently reported that homozygous TfR2(Y245X) mutant mice, which correspond to the TfR2(Y250X) mutation in humans, showed a phenotype similar to hereditary hemochromatosis. In this study, we further analyzed the phenotype as well as iron-related gene expression in these mice by comparing the TfR2-mutant and wild-type siblings. Northern blot analyses showed that the levels of expression of hepcidin mRNA in the liver were generally lower, whereas those of duodenal DMT1, the main transporter for uptake of dietary iron, were higher in the TfR2-mutant mice as compared to the wild-type siblings. Expression of hepcidin mRNA in the TfR2 mutant mice remained low even after intraperitoneal iron loading. In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA. These results suggest that up-regulation of hepcidin expression by inflammatory stimuli is independent of TfR2 and that TfR2 is upstream of hepcidin in the regulatory pathway of body iron homeostasis. (C) 2005 by The American Society of Hematology.