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Transferrin receptor 1 controls systemic iron homeostasis by fine-tuning hepcidin expression to hepatocellular iron load

Carine Fillebeen, Edouard Charlebois, John Wagner, Angeliki Katsarou, Jeannie Mui, Hojatollah Vali, Daniel Garcia-Santos, Prem Ponka, John Presley and Kostas Pantopoulos

Key points

  • TfrcAlb-Cre mice exhibit low hepatocellular iron and develop mild hypoferremia and microcytosis due to inappropriate hepcidin expression.

  • Tfr1 is essential for fine-tuning hepcidin responses to hepatocellular iron load but dispensable for basal iron supply to hepatocytes.

Abstract

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 (Tfrc-/-) 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 to that of control Tfrcfl/fl littermates, due to reduced capacity of Tfr1-deficient hepatocytes to internalize iron from transferrin. Even though liver Hamp mRNA and serum hepcidin levels do not differ among 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 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. We conclude 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.

  • Submitted May 10, 2018.
  • Accepted December 4, 2018.