Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice

We previously reported the disruption of the murine gene encoding the trans cription factor USF2 and its consequences on glucose-dependent gene regulat ion in the liver. We report here a peculiar phenotype of Usf2(-/-) mice tha t progressively develop multivisceral iron overload; plasma iron overcomes transferrin binding capacity, and nontransferrin-bound iron accumulates in various tissues including pancreas and heart. In contrast, the splenic iron content is strikingly lower in knockout animals than in controls. To ident ify genes that may account for the abnormalities of iron homeostasis in Usf 2(-/-) mice, we used suppressive subtractive hybridization between livers f rom Usf2(-/-) and wild-type mice. We isolated a cDNA encoding a peptide, he pcidin (also referred to as LEAP-1, for liver-expressed antimicrobial pepti de), that was very recently purified from human blood ultrafiltrate and fro m urine as a disulfide-bonded peptide exhibiting antimicrobial activity. Ac cumulation of iron in the liver has been recently reported to up-regulate h epcidin expression, whereas our data clearly show that a complete defect in hepcidin expression is responsible for progressive tissue iron overload. T he striking similarity of the alterations in iron metabolism between HFE kn ockout mice, a murine model of hereditary hemochromatosis, and the Usf2(-/- ) hepcidin-deficient mice suggests that hepcidin may function in the same r egulatory pathway as HFE. We propose that hepcidin acts as a signaling mole cule that is required in conjunction with HFE to regulate both intestinal i ron absorption and iron storage in macrophages.