Journal of Hepatology
Volume 54, Issue 1 , Pages 173-181 , January 2011

Hepcidin in human iron disorders: Therapeutic implications

Received 29 June 2010 ,Revised 3 August 2010 ,Accepted 19 August 2010.

References 

  1. 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(2–3):147–150
  2. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806–7810
  3. 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 overexpressed during iron overload. J Biol Chem. 2001;276(11):7811–7819
  4. 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(15):8780–8785
  5. Courselaud B, Pigeon C, Inoue Y, Inoue J, Gonzalez FJ, Leroyer P, et al. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. Cross-talk between C/EBP pathway and iron metabolism. J Biol Chem. 2002;277(43):41163–41170
  6. 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(7):4596–4601
  7. Bothwell TH. The control of iron absorption. Br J Haematol. 1968;14(5):453–456
  8. Bothwell TH, Hurtado AV, Donohue DM, Finch CA. Erythrokinetics. IV. The plasma iron turnover as a measure of erythropoiesis. Blood. 1957;12(5):409–427
  9. Finch CA. Iron Balance in Man. Nutr Rev. 1965;23:129–131
  10. Pietrangelo A. Hemochromatosis: an endocrine liver disease. Hepatology. 2007;46(4):1291–1301
  11. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2008;40(1):132–138
  12. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275(26):19906–19912
  13. 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(6771):776–781
  14. 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(2):299–309
  15. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093
  16. 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(1):328–333
  17. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18(7):2569–2578
  18. Vecchi C, Montosi G, Zhang K, Lamberti I, Duncan SA, Kaufman RJ, et al. ER stress controls iron metabolism through induction of hepcidin. Science. 2009;325(5942):877–880
  19. Oliveira SJ, Pinto JP, Picarote G, Costa VM, Carvalho F, Rangel M, et al. ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity. PLoS One. 2009;4(8):e6618
  20. 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(7):1037–1044
  21. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117(7):1926–1932
  22. Pinto JP, Ribeiro S, Pontes H, Thowfeequ S, Tosh D, Carvalho F, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood. 2008;111(12):5727–5733
  23. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096–1101
  24. Tanno T, Porayette P, Sripichai O, Noh SJ, Byrnes C, Bhupatiraju A, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181–186
  25. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088–1092
  26. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502–511
  27. 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(9):1271–1276
  28. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204–3209
  29. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109(1):353–358
  30. Pietrangelo A, Dierssen U, Valli L, Garuti C, Rump A, Corradini E, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132(1):294–300
  31. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2(6):399–409
  32. Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2008;4(1):33–41
  33. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117(7):1933–1939
  34. Verga Falzacappa MV, Casanovas G, Hentze MW, Muckenthaler MU. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med. 2008;86(5):531–540
  35. Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell. 2006;124(3):587–599
  36. 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(1):47–56
  37. Theurl I, Theurl M, Seifert M, Mair S, Nairz M, Rumpold H, et al. Autocrine formation of hepcidin induces iron retention in human monocytes. Blood. 2008;111(4):2392–2399
  38. De Domenico I, Zhang TY, Koening CL, Branch RW, London N, Lo E, et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest. 2010;120(7):2395–2405
  39. Corradini E, Babitt JL, Lin HY. The RGM/DRAGON family of BMP co-receptors. Cytokine Growth Factor Rev. 2009;20(5–6):389–398
  40. 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(1):77–82
  41. Lin L, Goldberg YP, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood. 2005;106(8):2884–2889
  42. Zhang AS, West AP, Wyman AE, Bjorkman PJ, Enns CA. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem. 2005;280(40):33885–33894
  43. Yang F, West AP, Allendorph GP, Choe S, Bjorkman PJ. Neogenin interacts with hemojuvelin through its two membrane-proximal fibronectin type III domains. Biochemistry. 2008;47(14):4237–4245
  44. Lee DH, Zhou LJ, Zhou Z, Xie JX, Jung JU, Liu Y, et al. Neogenin inhibits HJV secretion and regulates BMP induced hepcidin expression and iron homeostasis. Blood. 2010;115:3136–3145
  45. Xia Y, Babitt JL, Sidis Y, Chung RT, Lin HY. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood. 2008;111(10):5195–5204
  46. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531–539
  47. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112(4):1503–1509
  48. Mleczko-Sanecka K, Casanovas G, Ragab A, Breitkopf K, Muller A, Boutros M, et al. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood. 2010;115(13):2657–2665
  49. Andriopoulos B, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41(4):482–487
  50. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41(4):478–481
  51. Feder JN, Penny DM, Irrinki A, Lee VK, Lebrón JA, Watson N, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Nat Acad Sci USA. 1998;95(4):1472–1477
  52. 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(3):361–366
  53. 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(9358):669–673
  54. 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 the serum transferrin saturation and to non-transferrin-bound iron. Blood. 2003;102(1):371–376
  55. Vujic Spasic M, Kiss J, Herrmann T, Galy B, Martinache S, Stolte J, et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 2008;7(2):173–178
  56. Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos B, Lin HY, et al. Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology. 2009;137(4):1489–1497
  57. Kautz L, Meynard D, Besson-Fournier C, Darnaud V, Al Saati T, Coppin H, et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood. 2009;114(12):2515–2520
  58. 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(1):376–381
  59. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2-Hemochromatosis. Blood. 2005;105:1803–1806
  60. Griffiths WJ, Cox TM. Co-localization of the mammalian hemochromatosis gene product (HFE) and a newly identified transferrin receptor (TfR2) in intestinal tissue and cells. J Histochem Cytochem. 2003;51(5):613–624
  61. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281(39):28494–28498
  62. Waheed A, Britton RS, Grubb JH, Sly WS, Fleming RE. HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron. Arch Biochem Biophys. 2008;474(1):193–197
  63. Chen J, Chloupkova M, Gao J, Chapman-Arvedson TL, Enns CA. HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1-HFE interactions. J Biol Chem. 2007;282(51):36862–36870
  64. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7(3):205–214
  65. Pietrangelo A. Iron chelation beyond transfusion iron overload. Am J Hematol. 2007;82(Suppl. 12):1142–1146
  66. Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, et al. Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996;271(5254):1423–1427
  67. Bridle K, Cheung TK, Murphy T, Walters M, Anderson G, Crawford DG, et al. Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res. 2006;30(1):106–112
  68. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem. 2006;281(32):22974–22982
  69. Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008;134(1):226–238
  70. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis and treatment. Gastroenterology. 2010;139:393–408
  71. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399–408
  72. 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 haemochromatosis mapping to 7q22. Nat Genet. 2000;25(1):14–15
  73. Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JW, Breuning MH, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28(3):213–214
  74. Roetto A, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33(1):21–22
  75. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105(4):1803–1806
  76. Kattamis A, Papassotiriou I, Palaiologou D, Apostolakou F, Galani A, Ladis V, et al. The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major. Haematologica. 2006;91(6):809–812
  77. EASL. EASL Clinical Practice Guidelines on Hemochromatosis. J Hepatol 2010.
  78. Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, et al. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology. 2010;
  79. Kearney SL, Nemeth E, Neufeld EJ, Thapa D, Ganz T, Weinstein DA, et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer. 2007;48(1):57–63
  80. Weiss G. Iron metabolism in the anemia of chronic disease. Biochim Biophys Acta. 2009;1790(7):682–693
  81. Nemeth E. Targeting the hepcidin–ferroportin axis in the diagnosis and treatment of anemias. Adv Hematol. 2010;2010:750643
  82. Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis. 2010;55(4):726–741
  83. Zaritsky J, Young B, Wang HJ, Westerman M, Olbina G, Nemeth E, et al. Hepcidin–a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(6):1051–1056
  84. Elliott J, Mishler D, Agarwal R. Hyporesponsiveness to erythropoietin: causes and management. Adv Chronic Kidney Dis. 2009;16(2):94–100
  85. Melis MA, Cau M, Congiu R, Sole G, Barella S, Cao A, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica. 2008;93(10):1473–1479
  86. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40(5):569–571
  87. 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(10):3776–3781
  88. Chung A, Leo K, Wong G, Chuah K, Ren J, Lee C. Giant hepatocellular adenoma presenting with chronic iron deficiency anemia. Am J Gastroenterol. 2006;101(9):2160–2162
  89. Sasu BJ, Cooke KS, Arvedson TL, Plewa C, Ellison AR, Sheng J, et al. Anti-hepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood. 2010;115:3616–3624
  90. Hashizume M, Uchiyama Y, Horai N, Tomosugi N, Mihara M. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production. Rheumatol Int. 2010;30(7):917–923
  91. Kawabata H, Tomosugi N, Kanda J, Tanaka Y, Yoshizaki K, Uchiyama T. Anti-interleukin 6 receptor antibody tocilizumab reduces the level of serum hepcidin in patients with multicentric Castleman’s disease. Haematologica. 2007;92(6):857–858
  92. Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, et al. Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica. 2010;95(3):505–508
  93. Huang H, Constante M, Layoun A, Santos MM. Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli. Blood. 2009;113(15):3593–3599
  94. Weiss G, Theurl I, Eder S, Koppelstaetter C, Kurz K, Sonnweber T, et al. Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy. Eur J Clin Invest. 2009;39:883–890

☆ Disclosure: No conflict of interest to disclose.

PII: S0168-8278(10)00730-0

doi: 10.1016/j.jhep.2010.08.004

Journal of Hepatology
Volume 54, Issue 1 , Pages 173-181 , January 2011

Article Tools

* Image Usage & Resolution