A New Mouse Liver-specific Gene, Encoding a Protein Homologous to Human Antimicrobial Peptide Hepcidin, Is Overexpressed during Iron Overload*

By C. Pigeon, G. Ilyin, Brice Courselaud, P. Leroyer, B. Turlin, P. Brissot, O. Loréal. Journal of Biological Chemistry, 2001

1,735 citations recorded by the source corpus.

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 up-regulated under the condition of iron excess. By suppressive subtractive hybridization performed between livers from carbonyl iron-overloaded and control mice, we isolated a 225-base pair 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 (β2-microglobulin knockout mice) iron-overloaded mice. In addition, β2-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 an 83-amino acid protein presenting a strong homology in its C-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 toUSF2 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 lipopolysaccharide. Finally, to analyze the intracellular localization of the predicted protein, we used the green fluorescent protein chimera expression vectors. The murine green fluorescent protein-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 HEPCmight play a specific role during iron overload and exhibit additional functions distinct from its antimicrobial activity.

Subfields: Genetics, Hematology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/5bca22669e29b12322a887d619af228aaa9fad3f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. T. Ganz
2. E. Nemeth
3. S. Rivera
4. D. Richardson
5. D. Kalinowski
6. B. K. Pedersen
7. C. Keller
8. V. Gabayan

In Hematology

1. T. Ganz
2. E. Nemeth
3. S. Rivera
4. D. Richardson
5. D. Kalinowski
6. B. K. Pedersen
7. C. Keller
8. V. Gabayan

In Nutrition and Dietetics

1. T. Ganz
2. E. Nemeth
3. Tracey Rouault
4. B. K. Pedersen

Citations in the corpus

• Hepcidin and iron regulation, 10 years later. (2011, background): “32 On the basis of the work by many groups, a model of hepcidin regulation by iron has emerged (Figure 2) in which (1) the BMP receptor and its signaling components are at the core of the regulatory mechanism and control the transcription of hepcidin thorough the Smad pathway; (2) HJV is an iron-spe”
• The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer (2005, background): “Under conditions of iron overload, hepcidin is highly expressed in the liver (Pigeon et al., 2001).”
• A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. (2005, background): “Members of the transforming growth factor b (TGF-b) superfamily play numerous important functions in diverse developmental processes by regulating proliferation, differentiation, and apoptosis (reviewed in Derynck et al., 2001; Pollard, 2001; Wakefield et al., 2001).”
• Iron, brain ageing and neurodegenerative disorders (2004, background): “Recent investigations into the role of humoral factors in programming the enterocyte indicated that the main molecules involved are the antimicrobial peptide hepcidi”
• Systemic iron homeostasis. (2013, background): “7-kDa (25 amino acid) peptide (FIGURE 3) containing four disulfide bonds (132, 179, 186).”
• The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. (2002, positive): “Because the hepcidin mRNA level was reported to be upregulated by iron (5), we wondered whether the observed anemia-induced downregulation of hepcidin could be conversely explained by iron deficiency.”
• IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. (2004, positive): “Thus, hepcidin mRNA expression was increased in mice with diet-induced or genetically induced iron overload (3, 7) and decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen (8).”
• Mutations in HFE2 cause iron overload in chromosome 1q–linked juvenile hemochromatosis (2004, background): “HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolis”