Transferrin receptor 2: Continued expression in mouse liver in the face ofiron overload and in hereditary hemochromatosis

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder ch aracterized by excess absorption of dietary iron and progressive iron depos ition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite downregulation of the classical transferrin recepto r (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-lengt h murine EST encoding the mouse orthologue of the human TfR2. Although homo logous to murine TfR in the coding region, the TfR2 transcript does not con tain the iron-responsive elements found in the 3' untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models o f dietary iron overload (2% carbonyl iron), dietary iron deficiency (gastri c parietal cell ablation), and HH (HFE -/-). Northern blot analyses demonst rated distinct tissue-specific patterns of expression for TfR and TfR2, wit h TfR2 expressed highly only in liver where TfR expression is low. In situ hybridization demonstrated abundant TfR2 expression in hepatocytes. In cont rast to TfR, TfR2 expression in liver was not increased in iron deficiency. Furthermore, hepatic expression of TfR2 was not downregulated with dietary iron loading or in the HFE -/- model of HH. From these observations, we pr opose that TfR2 allows continued uptake of Tf-bound iron by hepatocytes eve n after TfR has been down-regulated by iron overload, and this uptake contr ibutes to the susceptibility of liver to iron loading in HH.