• 1
    Finch C. Regulators of iron balance in humans. Blood 1994;84:1697702.
  • 2
    Cavill I. Iron and erythropoietin in renal disease. Nephrol Dial Transplant 2002;17(Suppl. 5):1923.
  • 3
    Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:198695.
  • 4
    Frazer DM, Anderson GJ. Iron imports. I. Intestinal iron absorption and its regulation. Am J Physiol Gastrointest Liver Physiol 2005;289:G6315.
  • 5
    Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352:101123.
  • 6
    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:7838.
  • 7
    Falzacappa M, Muckenthaler M. Hepcidin: iron hormone and anti-microbial peptide. Gene 2005;364:3744.
  • 8
    Krijt J, Cmejla R, Sykora V, Vokurka M, Vyoral D, Necas E. Different expression pattern of hepcidin genes in the liver and pancreas of C57BL/6N and DBA/2N mice. J Hepatol 2004;40:8916.
  • 9
    Liu XB, Nguyen NB, Marquess KD, Yang F, Haile DJ. Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages. Blood Cells Mol Dis 2005;35:4756.
  • 10
    Fleming MD, Trenor CC 3rd, Su MA, Foernzler D, Beier DR, Dietrich WF et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997;16:3836.
  • 11
    Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997;388:4828.
  • 12
    Chen H, Su T, Attieh ZK, Fox TC, McKie AT, Anderson GJ et al. Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. Blood 2003;102:18939.
  • 13
    Frazer DM, Wilkins SJ, Becker EM, Murphy TL, Vulpe CD, McKie AT et al. A rapid decrease in the expression of DMT1 and Dcytb but not Ireg1 or hephaestin explains the mucosal block phenomenon of iron absorption. Gut 2003;52:3406.
  • 14
    Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 1998;95:114853.
  • 15
    Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000;275:1990612.
  • 16
    Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000;403:77681.
  • 17
    McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000;5:299309.
  • 18
    Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005;1:191200.
  • 19
    Canonne-Hergaux F, Donovan A, Delaby C, Wang HJ, Gros P. Comparative studies of duodenal and macrophage ferroportin proteins. Am J Physiol Gastrointest Liver Physiol 2006;290:G15663.
  • 20
    Anderson GJ, Frazer DM. Recent advances in intestinal iron transport. Curr Gastroenterol Rep 2005;7:36572.
  • 21
    Knutson MD, Vafa MR, Haile DJ, Wessling-Resnick M. Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood 2003;102:41917.
  • 22
    Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling-Resnick M. Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc Natl Acad Sci USA 2005;102:13248.
  • 23
    Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol 2003;38:6188.
  • 24
    Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 1997;37:51754.
  • 25
    Poss KD, Tonegawa S. Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 1997;94:1091924.
  • 26
    Delaby C, Pilard N, Hetet G, Driss F, Grandchamp B, Beaumont C et al. A physiological model to study iron recycling in macrophages. Exp Cell Res 2005;310:43 53.
  • 27
    Fraenkel PG, Traver D, Donovan A, Zahrieh D, Zon LI. Ferroportin 1 is required for normal iron cycling in zebrafish. J Clin Invest 2005;115:153241.
  • 28
    Yang F, Haile DJ, Wang X, Dailey LA, Stonehuerner JG, Ghio AJ. Apical location of ferroportin 1 in airway epithelia and its role in iron detoxification in the lung. Am J Physiol Lung Cell Mol Physiol 2005;289:L1423.
  • 29
    Wessling-Resnick M. Iron imports. III. Transfer of iron from the mucosa into circulation. Am J Physiol Gastrointest Liver Physiol 2006;290:G16.
  • 30
    Simovich MJ, Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Smith HK. Cellular location of proteins related to iron absorption and transport. Am J Hematol 2002;69:16470.
  • 31
    Frazer DM, Anderson GJ. The orchestration of body-iron intake: how and where do enterocytes receive their cues? Blood Cells Mol Dis 2003;30:28897.
  • 32
    Ganz T. Hepcidin in iron metabolism. Curr Opin Hematol 2004;11:2514.
  • 33
    Roy CN, Andrews NC. Anemia of inflammation: the hepcidin link. Curr Opin Hematol 2005;12:10711.
  • 34
    Shike H, Lauth X, Westerman ME, Ostland VE, Carlberg JM, Van Olst JC et al. Bass hepcidin is a novel antimicrobial peptide induced by bacterial challenge. Eur J Biochem 2002;269:22327.
  • 35
    Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:780610.
  • 36
    Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000;480:14750.
  • 37
    Kulaksiz H, Gehrke SG, Janetzko A, Rost D, Bruckner T, Kallinowski B et al. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut 2004;53:73543.
  • 38
    Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is over-expressed during iron overload. J Biol Chem 2001;276:78119.
  • 39
    Fleming RE, Bacon BR. Orchestration of iron homeostasis. N Engl J Med 2005;352:17414.
  • 40
    Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:103744.
  • 41
    Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D et al. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 2002;123:83544.
  • 42
    Ahmad KA, Ahmann JR, Migas MC, Waheed A, Britton RS, Bacon BR et al. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis 2002;29:3616.
  • 43
    Mazur A, Feillet-Coudray C, Romier B, Bayle D, Gueux E, Ruivard M et al. Dietary iron regulates hepatic hepcidin 1 and 2 mRNAs in mice. Metabolism 2003;52:122931.
  • 44
    Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003;101:24613.
  • 45
    Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:12716.
  • 46
    Beutler E. Unlocking the mysteries of iron homeostasis and of the anemia of chronic disease: is hepcidin the key? Blood 2003;102:775 (letter).
  • 47
    Laftah AH, Raja KB, Latunde-Dada GO, Vergi T, McKie AT, Simpson RJ et al. Effect of altered iron metabolism on markers of haem biosynthesis and intestinal iron absorption in mice. Ann Hematol 2005;84:17782.
  • 48
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:20903.
  • 49
    Delaby C, Pilard N, Goncalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood 2005;106:397984.
  • 50
    Nemeth E, Preza GC, Jung CL, Kaplan J, Waring AJ, Ganz T. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood 2006;107:32833.
  • 51
    Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron-uptake and hereditary hemochromatosis. J Biol Chem 2002;277:37597603.
  • 52
    Frazer DM, Inglis HR, Wilkins SJ, Millard KN, Steele TM, McLaren GD et al. Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut 2004;53:150915.
  • 53
    Latunde-Dada GO, Vulpe CD, Anderson GJ, Simpson RJ, McKie AT. Tissue-specific changes in iron metabolism genes in mice following phenylhydrazine-induced haemolysis. Biochim Biophys Acta 2004;1690:16976.
  • 54
    Miret S, Simpson RJ, McKie AT. Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr 2003;23:283301.
  • 55
    Laftah AH, Ramesh B, Simpson RJ, Solanky N, Bahram S, Schumann K et al. Effect of hepcidin on intestinal iron absorption in mice. Blood 2004;103:39404.
  • 56
    Rivera S, Nemeth E, Gabayan V, Lopez MA, Farshidi D, Ganz T. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood 2005;106:21969.
  • 57
    Viatte L, Nicolas G, Lou DQ, Bennoun M, Lesbordes-Brion JC, Canonne-Hergaux F et al. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice. Blood 2006 Dec 8: [Epub ahead of print].
  • 58
    Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001;98:87805.
  • 59
    Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002;99:4596601.
  • 60
    Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 2002;100:377681.
  • 61
    Rivera S, Liu L, Nemeth E, Gabayan V, Sorensen OE, Ganz T. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood 2005;105:1797802.
  • 62
    Viatte L, Lesbordes-Brion JC, Lou DQ, Bennoun M, Nicolas G, Kahn A et al. Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood 2005;105:48614.
  • 63
    Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest 2005;115:218791.
  • 64
    Mok H, Mendoza M, Prchal JT, Balogh P, Schumacher A. Dysregulation of ferroportin 1 interferes with spleen organogenesis in polycythaemia mice. Development 2004;131:487181.
  • 65
    Dallalio G, Law E, Means RT Jr. Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 2006;107:27024.
  • 66
    Anderson GJ, Frazer DM, Wilkins SJ, Becker EM, Millard KN, Murphy TL et al. Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption. Biochem Soc Trans 2002;30:7246.
  • 67
    Roy CN, Custodio AO, De Graaf J, Schneider S, Akpan I, Montross LK et al. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nat Genet 2004;36:4815.
  • 68
    Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood 2005;105:18036.
  • 69
    Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004;36:7782.
  • 70
    Lee P, Peng H, Gelbart T, Beutler E. The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes. Proc Natl Acad Sci USA 2004;101:92635.
  • 71
    Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 2005;102:190610.
  • 72
    Yeh KY, Yeh M, Glass J. Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat. Am J Physiol Gastrointest Liver Physiol 2004;286:G38594.
  • 73
    Alvarez-Hernandez X, Liceaga J, McKay IC, Brock JH. Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor. Lab Invest 1989;61:31922.
  • 74
    Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002;99:350516.
  • 75
    Maury CP, Andersson LC, Teppo AM, Partanen S, Juvonen E. Mechanism of anaemia in rheumatoid arthritis: demonstration of raised interleukin-1-beta concentrations in anaemic patients and of interleukin-1 mediated suppression of normal erythropoiesis and proliferation of human erythroleukaemia (HEL) cells in vitro. Ann Rheum Dis 1988;47:9728.
  • 76
    Beutler E, Waalen J, Gelbart T. Chronic inflammation does not appear to modify the homozygous hereditary hemochromatosis phenotype. Blood Cells Mol Dis 2005;35:3267.
  • 77
    Aoki CA, Rossaro L, Ramsamooj R, Brandhagen D, Burritt MF, Bowlus CL. Liver hepcidin mRNA correlates with iron stores, but not inflammation, in patients with chronic hepatitis C. J Clin Gastroenterol 2005;39:714.
  • 78
    OMIM. Online Mendelian Inheritance in Man. Available at: Accessed January 31, 2006.
  • 79
    Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DH et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003;361:66973.
  • 80
    Gehrke SG, Kulaksiz H, Herrmann T, Riedel HD, Bents K, Veltkamp C et al. Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to serum transferrin saturation and non-transferrin bound iron. Blood 2003;102:3716.
  • 81
    Muckenthaler M, Roy CN, Custodio AO, Minana B, DeGraaf J, Montross LK et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 2003;34:1027.
  • 82
    Kawabata H, Fleming RE, Gui D, Moon SY, Saitoh T, O’Kelly J et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 2005;105:37681.
  • 83
    Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP et al. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 2001;98:27149.
  • 84
    Kawabata H, Germain RS, Vuong PT, Nakamaki T, Said JW, Koeffler HP et al. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 2000;275:1661825.
  • 85
    West AP Jr, Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ. Comparison of the interaction of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem 2000;275:381358.
  • 86
    Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M et al. The gene TFR2 is mutated in a new type of haemachromatosis mapping to 7q22. Nat Genet 2000;25:145.
  • 87
    Pietrangelo A. Hereditary hemochromatosis – a new look at an old disease. N Engl J Med 2004;350:238397.
  • 88
    Pietrangelo A. Non-HFE Hemochromatosis. Semin Liver Dis 2005;25:45060.
  • 89
    Pietrangelo A, Caleffi A, Henrion J, Ferrara F, Corradini E, Kulaksiz H et al. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 2005;128:4709.
  • 90
    Cazzola M, Cremonesi L, Papaioannou M, Soriani N, Kioumi A, Charalambidou A et al. Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three-base pair deletion in the coding region of the ferroportin gene (SLC11A3). Br J Haematol 2002;119:53946.
  • 91
    Devalia V, Carter K, Walker AP, Perkins SJ, Worwood M, May A et al. Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 2002;100:6957.
  • 92
    Roetto A, Merryweather-Clarke AT, Daraio F, Livesey K, Pointon JJ, Barbabietola G et al. A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4. Blood 2002;100:7334.
  • 93
    Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW et al. Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 2002;100:6924.
  • 94
    Wallace DF, Clark RM, Harley HA, Subramaniam VN. Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis. J Hepatol 2004;40:7103.
  • 95
    Wallace DF, Browett P, Wong P, Kua H, Ameratunga R, Subramaniam VN. Identification of ferroportin disease in the Indian subcontinent. Gut 2005;54:5678.
  • 96
    Arden KE, Wallace DF, Dixon JL, Summerville L, Searle JW, Anderson GJ et al. A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient. Gut 2003;52:12157.
  • 97
    Hetet G, Devaux I, Soufir N, Grandchamp B, Beaumont C. Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and three new ferroportin (slc11A3) mutations. Blood 2003;102:190410.
  • 98
    Jouanolle AM, Douabin-Gicquel V, Halimi C, Loreal O, Fergelot P, Delacour T et al. Novel mutation in ferroportin1 gene is associated with autosomal dominant iron overload. J Hepatol 2003;39:2869.
  • 99
    Rivard SR, Lanzara C, Grimard D, Carella M, Simard H, Ficarella R et al. Autosomal dominant reticuloendothelial iron overload (HFE type 4) due to a new missense mutation in the ferroportin1 gene (SLC11A3) in a large French-Canadian family. Haematologica 2003;88:8246.
  • 100
    Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis 2004;32:1318.
  • 101
    Kohgo Y. A novel ferroportin disease in a Japanese patient. Intern Med 2005;44:3934.
  • 102
    Morris TJ, Litvinova MM, Ralston D, Mattman A, Holmes D, Lockitch G. A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis. Blood Cells Mol Dis 2005;35:30914.
  • 103
    Sham RL, Phatak PD, West C, Lee P, Andrews C, Beutler E. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features. Blood Cells Mol Dis 2005;34:15761.
  • 104
    Subramaniam VN, Wallace DF, Dixon JL, Fletcher LM, Crawford DH. Ferroportin disease due to the A77D mutation in Australia. Gut 2005;54:10489.
  • 105
    De Domenico I, Ward DM, Nemeth E, Vaughn MB, Musci G, Ganz T et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci USA 2005;102:895560.
  • 106
    Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 2005;106:10927.
  • 107
    Kemna E, Pickkers P, Nemeth E, Van Der Hoeven H, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005;106:18646.
  • 108
    Peyssonnaux C, Zinkernagel AS, Datta V, Lauth X, Johnson RS, Nizet V. Blood 2006 Jan 3: Epub ahead of print.