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

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 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. 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.

Hepcidin secretion was not directly proportional to intracellular iron-loading in recombinant-TfR1 HepG2 cells: short communication

“…Interestingly, these cells resemble the scenario created due to the mutation in TFRC (gene encoding TfR1) in human, as recently identified, which leads to increased cell-surface TfR1 [49]. Our data may partly support the recently published data indicating the essential role of TfR1 in tuning hepcidin expression based on the level of iron-loading in hepatocytes and reiterates the inhibitory function of TfR1 on hepcidin expression [50].…”

Transferrin receptor 1 levels at the cell surface influence the susceptibility of newborn piglets to PEDV infection

“…As an example, many HIV-positive individuals suffer from iron deficiency [5] which hinders their ability to limit infection, especially when the virus attacks immune cells [6,7]. Iron-loaded transferrin binds with transferrin receptor 1 (TfR1) on the surface of cells, which then delivers the iron into the cell [8]. TfR1 mediates cellular iron uptake, and as such, is a key molecule in cellular iron homeostasis and plays a central part in the homeostasis of the intestine [9,10].…”

Expression and Functional Analysis of Hepcidin from Mandarin Fish (Siniperca chuatsi)

“…Iron loading can induce hepcidin expression in vivo in mice and humans [12]. Ferroportin 1 (FPN1) [13], transferrin receptor 1 (TFR1) [14], and ferritin (FTN) [15] are three important genes regulating iron balance; hepcidin regulates iron balance by internalizing and degrading FPN1 on the basolateral membrane (BLM) of cells to inhibit iron output, thereby controlling extracellular iron concentration and systemic iron balance [16,17]. Hepcidin expression is also strongly induced during infection and inflammation, and the regulatory role of hepcidin in the inflammatory response is supported by many studies on the pathogenesis of infection [18,19,20].…”