Hepatocyte Transferrin Receptor 1 Linked With Iron Homeostasis, Showing Implications for Beta-Thalassemia

In a study of the regulation of iron homeostasis, researchers characterized relationships between hepatocyte transferrin receptor 1 (TfR1), hemochromatosis protein HFE, and hepcidin in mice. The researchers reported their findings in the journal Blood.

TfR1 is involved in the delivery of iron into cells from iron-bound transferrin. However, it has also been suggested that TfR1 may be involved in iron homeostasis through an impact on expression of hepcidin, a hormone that is key to regulating systemic iron homeostasis. Binding of hepcidin to ferroportin limits the export of iron into circulation from dietary sources or stores of iron. HFE has a role in enhancing hepcidin expression, and it has been suggested that hepatocyte TfR1 may affect hepcidin expression by binding with HFE.

The researchers evaluated the role of hepatocyte TfR1 with a murine model, in which hepatocyte Tfrc was knocked out from mice. These mice were crossed with mice having Cre recombinase activity utilizing an albumin promoter, ultimately generating Tfrc^fl/fl;Alb-Cre⁺ mice. A control group included Tfrc^fl/fl;Alb-Cre^– mice that were fed a low-iron diet.

In some mice, Hfe was additionally knocked out, or a heterozygous B1/B2 globin gene deletion was constructed in a manner corresponding to a beta-thalassemia intermedia model. The researchers performed various analyses with tissue and/or serum samples from the mouse models to investigate relationships between HFE, hepatocyte TfR1, hepcidin regulation, and iron overload in beta-thalassemia.

The Tfrc^fl/fl;Alb-Cre⁺ mice showed lower levels of serum and liver iron in comparison with the Tfrc^fl/fl;Alb-Cre^– control mice. They also showed other differences, such as mildly decreased levels of hematocrit, mean cell hemoglobin, and mean cell volume relative to the controls. They also showed higher levels of erythropoietin and erythroferrone. Additionally, their hepcidin transcript levels remained stable, but this level was higher than expected in comparison with their serum and liver iron levels and erythroferrone levels. Ultimately, when normalized to iron or erythroferrone levels, the hepcidin transcript levels were higher with these mice than in the control mice.

In mice with Hfe knocked out, there was no apparent change in iron phenotype with removal of hepatocyte Trfc. Additionally, higher serum iron was associated with increased hepcidin expression in the Tfrc^fl/fl;Alb-Cre⁺ mice, compared with the Tfrc^fl/fl;Alb-Cre^– control mice.

Acute erythropoietin injection for 9 or 15 hours was associated with similar levels of suppression of hepcidin in both the Tfrc^fl/fl;Alb-Cre+^– mice and the Tfrc^fl/fl;Alb-Cre^– control mice, suggesting that erythropoietin-mediated hepcidin suppression can occur independently of hepatocyte TfR1. However, in the beta-thalassemia intermedia model, deletion of hepatocyte Trfc was associated with less hepcidin suppression and a reduction in liver iron loading.

“In conclusion, our data demonstrate that the major function of hepatocyte TfR1 in iron homeostasis is to interact with HFE to regulate hepcidin,” the researchers wrote in their report. “Although it does not impact hepcidin suppression by acute erythropoietin injection, hepatocyte TfR1 does contribute to hepcidin suppression and liver iron overload in murine [beta-]thalassemia,” they also noted.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Xiao X, Moschetta GA, Xu Y, et al. Regulation of iron homeostasis by hepatocyte TfR1 requires HFE and contributes to hepcidin suppression in β-thalassemia. Blood. 2023;141(4):422-432. doi:10.1182/blood.2022017811