Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia

海西定 肝细胞 内分泌学 内科学 遗传性血色病 促红细胞生成素 转铁蛋白受体 无效红细胞生成 血色病 红细胞生成 生物 转铁蛋白 化学 贫血 医学 生物化学 体外
作者
Xia Xiao,Gillian A. Moschetta,Yang Xu,Allison L. Fisher,Víctor M. Alfaro‐Magallanes,Som Dev,Chia‐Yu Wang,Jodie L. Babitt
出处
期刊:Blood [American Society of Hematology]
卷期号:141 (4): 422-432 被引量:16
标识
DOI:10.1182/blood.2022017811
摘要

Abstract Transferrin receptor 1 (TfR1) performs a critical role in cellular iron uptake. Hepatocyte TfR1 is also proposed to influence systemic iron homeostasis by interacting with the hemochromatosis protein HFE to regulate hepcidin production. Here, we generated hepatocyte Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), either alone or together with Hfe knockout or β-thalassemia, to investigate the extent to which hepatocyte TfR1 function depends on HFE, whether hepatocyte TfR1 impacts hepcidin regulation by serum iron and erythropoietic signals, and its contribution to hepcidin suppression and iron overload in β-thalassemia. Compared with Tfrcfl/fl;Alb-Cre− controls, Tfrcfl/fl;Alb-Cre+ mice displayed reduced serum and liver iron; mildly reduced hematocrit, mean cell hemoglobin, and mean cell volume; increased erythropoietin and erythroferrone; and unchanged hepcidin levels that were inappropriately high relative to serum iron, liver iron, and erythroferrone levels. However, ablation of hepatocyte Tfrc had no impact on iron phenotype in Hfe knockout mice. Tfrcfl/fl;Alb-Cre+ mice also displayed a greater induction of hepcidin by serum iron compared with Tfrcfl/fl;Alb-Cre− controls. Finally, although acute erythropoietin injection similarly reduced hepcidin in Tfrcfl/fl;Alb-Cre+ and Tfrcfl/fl;Alb-Cre− mice, ablation of hepatocyte Tfrc in a mouse model of β-thalassemia intermedia ameliorated hepcidin deficiency and liver iron loading. Together, our data suggest that the major nonredundant function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin. This regulatory pathway is modulated by serum iron and contributes to hepcidin suppression and iron overload in murine β-thalassemia.
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