Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load
Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load
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DOI：
10.1182/blood-2018-05-850404
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发表时间：
2019-01-24
期刊：
影响因子：
20.3
通讯作者：
Pantopoulos, Kostas
中科院分区：
文献类型：
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作者：
Fillebeen, Carine;Charlebois, Edouard;Pantopoulos, Kostas
转铁蛋白受体 1 (Tfr1) 介导发育中的红细胞和其他细胞类型对循环转铁蛋白结合铁的吸收。 Tfr1 敲除 (Tfrc2/2) 小鼠的胚胎致死表型和几种组织特异性敲除的病理学凸显了其关键的生理功能。我们生成了 Tfr1 肝细胞特异性消融的 TfrcAlb-Cre 小鼠，以探索对肝细胞和全身铁稳态的影响。 TfrcAlb-Cre 小鼠是存活的并且没有表现出任何明显的肝脏病理学。然而，由于Tfr1缺陷的肝细胞内化转铁蛋白中的铁的能力降低，因此与对照Tfrcfl/fl同窝小鼠相比，它们的肝脏铁含量(LIC)较低。尽管 TfrcAlb-Cre 和 Tfrcfl/fl 小鼠之间肝脏 Hamp 信使 RNA (mRNA) 和血清铁调素水平没有差异，但前者的 Hamp/LIC 和铁调素/LIC 比率显着较高。重要的是，这伴随着适度的低铁血症和小红细胞增多症，并且它使 TfrcAlb-Cre 小鼠容易患缺铁性贫血。 TfrcAlb-Cre 小鼠在饮食铁操作或全转铁蛋白注射后适当调节 Hamp 表达。 Holo-转铁蛋白还会触发原代 TfrcAlb-Cre 肝细胞中 Hamp mRNA、铁蛋白和 Tfr2 的正确诱导。我们进一步表明，这些细胞可以从 59Fe-转铁蛋白获取 59Fe，大概是通过 Tfr2。我们的结论是，Tfr1 对于基础肝细胞铁供应来说是多余的，但对于根据肝细胞铁负荷微调铁调素反应至关重要。我们的数据与 Tfr1 通过与 Hfe 相互作用对铁调素信号传导的抑制功能一致。此外，他们强调肝细胞 Tfr1 作为细胞和全身铁调节途径之间的联系。
Transferrin receptor 1 (Tfr1) mediates uptake of circulating transferrin- bound iron to developing erythroid cells and other cell types. Its critical physiological function is highlighted by the embryonic lethal phenotype of Tfr1- knockout (Tfrc2/2) mice and the pathologies of several tissue- specific knockouts. We generated TfrcAlb- Cre mice bearing hepatocyte- specific ablation of Tfr1 to explore implications in hepatocellular and systemic iron homeostasis. TfrcAlb- Cre mice are viable and do not display any apparent liver pathology. Nevertheless, their liver iron content (LIC) is lower compared with that of control Tfrcfl/fl littermates as a result of the reduced capacity of Tfr1- deficient hepatocytes to internalize iron from transferrin. Even though liver Hamp messenger RNA (mRNA) and serum hepcidin levels do not differ between TfrcAlb- Cre and Tfrcfl/fl mice, Hamp/LIC and hepcidin/LIC ratios are significantly higher in the former. Importantly, this is accompanied by modest hypoferremia and microcytosis, and it predisposes TfrcAlb- Cre mice to iron-deficiency anemia. TfrcAlb-Cre mice appropriately regulate Hamp expression following dietary iron manipulations or holo-transferrin injection. Holo-transferrin also triggers proper induction of Hamp mRNA, ferritin, and Tfr2 in primary TfrcAlb-Cre hepatocytes. We further show that these cells can acquire 59Fe from 59Fe-transferrin, presumably via Tfr2. Weconclude that Tfr1 is redundant for basal hepatocellular iron supply but essential for fine-tuning hepcidin responses according to the iron load of hepatocytes. Our data are consistent with an inhibitory function of Tfr1 on iron signaling to hepcidin via its interaction with Hfe. Moreover, they highlight hepatocellular Tfr1 as a link between cellular and systemic iron-regulatory pathways.