Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis

Transferrin receptor 2 (TfR2) is a mem-brane glycoprotein that mediates cellular iron uptake from holotransferrin. Homozy-gous mutations of this gene cause one form of hereditary hemochromatosis in humans. We recently reported that ho-mozygous TfR2(Y245X) mutant mice, which correspond to the TfR2(Y250X) mu-tation in humans, showed a phenotype similar to hereditary hemochromatosis. In this study, we further analyzed the phenotype as well as iron-related gene expression in these mice by comparing the TfR2-mutant and wild-type siblings. Northern blot analyses showed that the levels of expression of hepcidin mRNA in the liver were generally lower, whereas those of duodenal DMT1, the main trans-porter for uptake of dietary iron, were higher in the TfR2-mutant mice as com-pared to the wild-type siblings. Expres-sion of hepcidin mRNA in the TfR2 mutant mice remained low even after intraperito-neal iron loading. In isolated hepatocytes from both wild-type and TfR2 mutant mice, interleukin-6 and lipopolysaccharide each induced expression of hepcidin mRNA. These results suggest that up-regulation of hepcidin expression by inflammatory stimuli is independent of TfR2 and that TfR2 is upstream of hepcidin in the regu-latory pathway of body iron homeostasis