Transferrin receptor 2 (Tfr2) is necessary for hepcidin induction in mice with hepatocyte-specific transferrin receptor 1 (Tfr1) deficiency Free

In hepatocytes, transferrin receptor 1 (Tfr1) does not have a major role in iron acquisition but rather controls signaling to the iron hormone hepcidin via its interaction with the hemochromatosis protein Hfe. Hepatocellular Tfr2, a Tfr1 homologue, operates as an iron sensor and direct regulator of hepcidin. We generated Tfrc^Alb-Cre;Tfr2^Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study implications in iron homeostasis. These animals are viable and phenocopy Tfr2^Alb-Cre mice by developing systemic iron overload. Only Tfr1-proficient primary hepatocytes from Tfrc^fl/fl;Tfr2^fl/fl and Tfr2^Alb-Cre mice could internalize fluorescent AF647-transferrin, arguing against a significant contribution of Tfr2 in uptake of transferrin-bound iron. After prolonged (12 weeks) dietary iron restriction, Tfr2-deficient livers from Tfrc^Alb-Cre;Tfr2^Alb-Cre and Tfr2^Alb-Cre mice had indistinguishably low Hamp mRNA levels and iron content, even though Tfr1 was robustly upregulated in the latter. Under these conditions, Tfr2-proficient livers from Tfrc^Alb-Cre mice had significantly higher Hamp mRNA levels, presumably because Tfr1 disruption “liberates” Hfe. Following short-term (6 h) exposure of iron-deficient animals to a high-iron diet, iron-dependent Hamp mRNA induction was evident in Tfrc^Alb-Cre but not in Tfrc^Alb-Cre;Tfr2^Alb-Cre mice. These findings suggest that “liberated” active Hfe can only induce hepcidin in the presence of Tfr2. Our data demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, while Tfr2 is essential for iron signaling to hepcidin in Tfr1-deficient hepatocytes.