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Papers In Press, published online ahead of print December 11, 2000
J. Biol. Chem, 10.1074/jbc.M008923200
Submitted on September 29, 2000
Revised on December 1, 2000
Accepted on December 11, 2000
U522, INSERM, Rennes 35033
Corresponding Author: christelle.pigeon{at}rennes.inserm.fr
Considering that the development of hepatic lesions related to iron overload diseases might be a result of abnormally expressed hepatic genes, we searched for new genes upregulated under condition of iron excess. By suppressive subtractive hybridization performed between livers from carbonyl-iron overloaded and control mice, we isolated a 225 bp cDNA. By northern blot analysis, the corresponding mRNA was confirmed to be overexpressed in livers of experimentally (carbonyl-iron and iron-dextran treated mice) and spontaneously (2 microglobulin knockout mice) iron overloaded mice. In addition, 2 microglobulin knockout mice fed with a low iron content diet exhibited a decrease of hepatic mRNA expression. The murine full length cDNA was isolated and was found to encode a 83 amino acid protein presenting a strong homology in its carboxy-terminal region to the human antimicrobial peptide hepcidin. In addition, we cloned the corresponding rat and human orthologue cDNAs. Both mouse and human genes named HEPC are constituted of 3 exons and 2 introns and are located on chromosome 7 and 19 respectively in close proximity to Usf2 gene. In mouse and human, HEPC mRNA was predominantly expressed in the liver. During both in vivo and in vitro studies, HEPC mRNA expression was enhanced in mouse hepatocytes under the effect of LPS. Finally, to analyze the intracellular localization of the predicted protein, we used the GFP chimera expression vectors. The murine GFP-prohepcidin protein was exclusively localized in the nucleus. When the putative nuclear localization signal was deleted, the resulting protein was addressed to the cytoplasm. Taken together, our data strongly suggest that the product of the new liver specific gene HEPC might play a specific role during iron overload and exhibit additional functions distinct from its antimicrobial activity.
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