Hepcidin in human iron disorders: Therapeutic implications

Journal of Hepatology

Volumn 54, Issue 1, 2011, Pages 173-181

  Pietrangelo, Antonello ^a  

^a UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

Author keywords

BMPs; Bone morphogenetic proteins; Ferroportin; FPN; HAMP; HC; Hemochromatosis; Hemojuvelin; Hepcidin gene; HJV; LEAP 1; Liver expressed antimicrobial protein; Repulsive guidance molecules; RGMs; Tf; TfR2; Transferrin; Transferrin receptor 2

Indexed keywords

FERROPORTIN; HEPCIDIN; IRON; RECOMBINANT ERYTHROPOIETIN;

ANEMIA; HEMOCHROMATOSIS; HORMONAL REGULATION; HORMONE SYNTHESIS; HUMAN; IRON DEFICIENCY; IRON DEFICIENCY ANEMIA; IRON METABOLISM DISORDER; IRON OVERLOAD; IRON THERAPY; LIVER ADENOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; THALASSEMIA;

ANEMIA, IRON-DEFICIENCY; ANTIMICROBIAL CATIONIC PEPTIDES; BONE MORPHOGENETIC PROTEINS; CATION TRANSPORT PROTEINS; HEMOCHROMATOSIS; HUMANS; IRON; IRON OVERLOAD; LIVER; MODELS, BIOLOGICAL; SIGNAL TRANSDUCTION; THALASSEMIA;

EID: 78649634981     PISSN: 01688278     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jhep.2010.08.004     Document Type: Review

References (94)

1. A. Krause, S. Neitz, H.J. Magert, A. Schulz, W.G. Forssmann, and P. Schulz-Knappe LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity FEBS Lett 480 2-3 2000 147 150
2. C.H. Park, E.V. Valore, A.J. Waring, and T. Ganz Hepcidin, a urinary antimicrobial peptide synthesized in the liver J Biol Chem 276 11 2001 7806 7810
3. C. Pigeon, G. Ilyin, B. Courselaud, P. Leroyer, B. Turlin, and P. Brissot A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload J Biol Chem 276 11 2001 7811 7819
4. G. Nicolas, M. Bennoun, I. Devaux, C. Beaumont, B. Grandchamp, and A. Kahn Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice Proc Natl Acad Sci USA 98 15 2001 8780 8785
5. B. Courselaud, C. Pigeon, Y. Inoue, J. Inoue, F.J. Gonzalez, and P. Leroyer 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 277 43 2002 41163 41170
6. G. Nicolas, M. Bennoun, A. Porteu, S. Mativet, C. Beaumont, and B. Grandchamp Severe iron deficiency anemia in transgenic mice expressing liver hepcidin Proc Natl Acad Sci USA 99 7 2002 4596 4601
7. T.H. Bothwell The control of iron absorption Br J Haematol 14 5 1968 453 456
8. T.H. Bothwell, A.V. Hurtado, D.M. Donohue, and C.A. Finch Erythrokinetics. IV. The plasma iron turnover as a measure of erythropoiesis Blood 12 5 1957 409 427
9. C.A. Finch Iron Balance in Man Nutr Rev 23 1965 129 131
10. A. Pietrangelo Hemochromatosis: an endocrine liver disease Hepatology 46 4 2007 1291 1301
11. E.V. Valore, and T. Ganz Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin Blood Cells Mol Dis 40 1 2008 132 138
12. S. Abboud, and D.J. Haile A novel mammalian iron-regulated protein involved in intracellular iron metabolism J Biol Chem 275 26 2000 19906 19912
13. A. Donovan, A. Brownlie, Y. Zhou, J. Shepard, S.J. Pratt, and J. Moynihan Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter Nature 403 6771 2000 776 781
14. A.T. McKie, P. Marciani, A. Rolfs, K. Brennan, K. Wehr, and D. Barrow A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation Mol Cell 5 2 2000 299 309
15. E. Nemeth, M.S. Tuttle, J. Powelson, M.B. Vaughn, A. Donovan, and D.M. Ward Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization Science 306 5704 2004 2090 2093
16. E. Nemeth, G.C. Preza, C.L. Jung, J. Kaplan, A.J. Waring, and T. Ganz The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study Blood 107 1 2006 328 333
17. I. De Domenico, D.M. Ward, C. Langelier, M.B. Vaughn, E. Nemeth, and W.I. Sundquist The molecular mechanism of hepcidin-mediated ferroportin down-regulation Mol Biol Cell 18 7 2007 2569 2578
18. C. Vecchi, G. Montosi, K. Zhang, I. Lamberti, S.A. Duncan, and R.J. Kaufman ER stress controls iron metabolism through induction of hepcidin Science 325 5942 2009 877 880
19. S.J. Oliveira, J.P. Pinto, G. Picarote, V.M. Costa, F. Carvalho, and M. Rangel ER stress-inducible factor CHOP affects the expression of hepcidin by modulating C/EBPalpha activity PLoS One 4 8 2009 e6618
20. G. Nicolas, C. Chauvet, L. Viatte, J.L. Danan, X. Bigard, and I. Devaux The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation J Clin Invest 110 7 2002 1037 1044
21. C. Peyssonnaux, A.S. Zinkernagel, R.A. Schuepbach, E. Rankin, S. Vaulont, and V.H. Haase Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs) J Clin Invest 117 7 2007 1926 1932
22. J.P. Pinto, S. Ribeiro, H. Pontes, S. Thowfeequ, D. Tosh, and F. Carvalho Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha Blood 111 12 2008 5727 5733
23. T. Tanno, N.V. Bhanu, P.A. Oneal, S.H. Goh, P. Staker, and Y.T. Lee High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin Nat Med 13 9 2007 1096 1101
24. T. Tanno, P. Porayette, O. Sripichai, S.J. Noh, C. Byrnes, and A. Bhupatiraju Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells Blood 114 1 2009 181 186
25. X. Du, E. She, T. Gelbart, J. Truksa, P. Lee, and Y. Xia The serine protease TMPRSS6 is required to sense iron deficiency Science 320 5879 2008 1088 1092
26. L. Silvestri, A. Pagani, A. Nai, I. De Domenico, J. Kaplan, and C. Camaschella The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin Cell Metab 8 6 2008 502 511
27. E. Nemeth, S. Rivera, V. Gabayan, C. Keller, S. Taudorf, and B.K. Pedersen IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin J Clin Invest 113 9 2004 1271 1276
28. D.M. Wrighting, and N.C. Andrews Interleukin-6 induces hepcidin expression through STAT3 Blood 108 9 2006 3204 3209
29. M.V. Verga Falzacappa, M. Vujic Spasic, R. Kessler, J. Stolte, M.W. Hentze, and M.U. Muckenthaler STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation Blood 109 1 2007 353 358
30. A. Pietrangelo, U. Dierssen, L. Valli, C. Garuti, A. Rump, and E. Corradini STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo Gastroenterology 132 1 2007 294 300
31. R.H. Wang, C. Li, X. Xu, Y. Zheng, C. Xiao, and P. Zerfas A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression Cell Metab 2 6 2005 399 409
32. P.B. Yu, C.C. Hong, C. Sachidanandan, J.L. Babitt, D.Y. Deng, and S.A. Hoyng Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism Nat Chem Biol 4 1 2008 33 41
33. J.L. Babitt, F.W. Huang, Y. Xia, Y. Sidis, N.C. Andrews, and H.Y. Lin Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance J Clin Invest 117 7 2007 1933 1939
34. M.V. Verga Falzacappa, G. Casanovas, M.W. Hentze, and M.U. Muckenthaler 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 86 5 2008 531 540
35. K. Zhang, X. Shen, J. Wu, K. Sakaki, T. Saunders, and D.T. Rutkowski Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response Cell 124 3 2006 587 599
36. X.B. Liu, N.B. Nguyen, K.D. Marquess, F. Yang, and D.J. Haile Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages Blood Cells Mol Dis 35 1 2005 47 56
37. I. Theurl, M. Theurl, M. Seifert, S. Mair, M. Nairz, and H. Rumpold Autocrine formation of hepcidin induces iron retention in human monocytes Blood 111 4 2008 2392 2399
38. I. De Domenico, T.Y. Zhang, C.L. Koening, R.W. Branch, N. London, and E. Lo Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice J Clin Invest 120 7 2010 2395 2405
39. E. Corradini, J.L. Babitt, and H.Y. Lin The RGM/DRAGON family of BMP co-receptors Cytokine Growth Factor Rev 20 5-6 2009 389 398
40. G. Papanikolaou, M.E. Samuels, E.H. Ludwig, M.L. MacDonald, P.L. Franchini, and M.P. Dube Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis Nat Genet 36 1 2004 77 82
41. L. Lin, Y.P. Goldberg, and T. Ganz Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin Blood 106 8 2005 2884 2889
42. A.S. Zhang, A.P. West Jr., A.E. Wyman, P.J. Bjorkman, and C.A. Enns Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells J Biol Chem 280 40 2005 33885 33894
43. F. Yang, A.P. West Jr., G.P. Allendorph, S. Choe, and P.J. Bjorkman Neogenin interacts with hemojuvelin through its two membrane-proximal fibronectin type III domains Biochemistry 47 14 2008 4237 4245
44. D.H. Lee, L.J. Zhou, Z. Zhou, J.X. Xie, J.U. Jung, and Y. Liu Neogenin inhibits HJV secretion and regulates BMP induced hepcidin expression and iron homeostasis Blood 115 2010 3136 3145
45. Y. Xia, J.L. Babitt, Y. Sidis, R.T. Chung, and H.Y. Lin Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin Blood 111 10 2008 5195 5204
46. J.L. Babitt, F.W. Huang, D.M. Wrighting, Y. Xia, Y. Sidis, and T.A. Samad Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression Nat Genet 38 5 2006 531 539
47. L. Kautz, D. Meynard, A. Monnier, V. Darnaud, R. Bouvet, and R.H. Wang Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver Blood 112 4 2008 1503 1509
48. K. Mleczko-Sanecka, G. Casanovas, A. Ragab, K. Breitkopf, A. Muller, and M. Boutros SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression Blood 115 13 2010 2657 2665
49. B. Andriopoulos Jr., E. Corradini, Y. Xia, S.A. Faasse, S. Chen, and L. Grgurevic BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism Nat Genet 41 4 2009 482 487
50. D. Meynard, L. Kautz, V. Darnaud, F. Canonne-Hergaux, H. Coppin, and M.P. Roth Lack of the bone morphogenetic protein BMP6 induces massive iron overload Nat Genet 41 4 2009 478 481
51. J.N. Feder, D.M. Penny, A. Irrinki, V.K. Lee, J.A. Lebrón, and N. Watson The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding Proc Nat Acad Sci USA 95 4 1998 1472 1477
52. K.A. Ahmad, J.R. Ahmann, M.C. Migas, A. Waheed, R.S. Britton, and B.R. Bacon Decreased liver hepcidin expression in the Hfe knockout mouse Blood Cells Mol Dis 29 3 2002 361 366
53. K.R. Bridle, D.M. Frazer, S.J. Wilkins, J.L. Dixon, D.M. Purdie, and D.H. Crawford Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis Lancet 361 9358 2003 669 673
54. S.G. Gehrke, H. Kulaksiz, T. Herrmann, H.D. Riedel, K. Bents, and C. Veltkamp Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron Blood 102 1 2003 371 376
55. M. Vujic Spasic, J. Kiss, T. Herrmann, B. Galy, S. Martinache, and J. Stolte Hfe acts in hepatocytes to prevent hemochromatosis Cell Metab 7 2 2008 173 178
56. E. Corradini, C. Garuti, G. Montosi, P. Ventura, B. Andriopoulos Jr., and H.Y. Lin Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis Gastroenterology 137 4 2009 1489 1497
57. L. Kautz, D. Meynard, C. Besson-Fournier, V. Darnaud, T. Al Saati, and H. Coppin BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression Blood 114 12 2009 2515 2520
58. H. Kawabata, R.E. Fleming, D. Gui, S.Y. Moon, T. Saitoh, and J. O'Kelly Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis Blood 105 1 2005 376 381
59. E. Nemeth, A. Roetto, G. Garozzo, T. Ganz, and C. Camaschella Hepcidin is decreased in TFR2-Hemochromatosis Blood 105 2005 1803 1806
60. W.J. Griffiths, and T.M. Cox Co-localization of the mammalian hemochromatosis gene product (HFE) and a newly identified transferrin receptor (TfR2) in intestinal tissue and cells J Histochem Cytochem 51 5 2003 613 624
61. T. Goswami, and N.C. Andrews Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing J Biol Chem 281 39 2006 28494 28498
62. A. Waheed, R.S. Britton, J.H. Grubb, W.S. Sly, and R.E. Fleming HFE association with transferrin receptor 2 increases cellular uptake of transferrin-bound iron Arch Biochem Biophys 474 1 2008 193 197
63. J. Chen, M. Chloupkova, J. Gao, T.L. Chapman-Arvedson, and C.A. Enns HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1-HFE interactions J Biol Chem 282 51 2007 36862 36870
64. P.J. Schmidt, P.T. Toran, A.M. Giannetti, P.J. Bjorkman, and N.C. Andrews The transferrin receptor modulates hfe-dependent regulation of hepcidin expression Cell Metab 7 3 2008 205 214
65. A. Pietrangelo Iron chelation beyond transfusion iron overload Am J Hematol 82 Suppl. 12 2007 1142 1146
66. V. Campuzano, L. Montermini, M.D. Molto, L. Pianese, M. Cossee, and F. Cavalcanti Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion Science 271 5254 1996 1423 1427
67. K. Bridle, T.K. Cheung, T. Murphy, M. Walters, G. Anderson, and D.G. Crawford Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease Alcohol Clin Exp Res 30 1 2006 106 112
68. D.D. Harrison-Findik, D. Schafer, E. Klein, N.A. Timchenko, H. Kulaksiz, and D. Clemens Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression J Biol Chem 281 32 2006 22974 22982
69. S. Nishina, K. Hino, M. Korenaga, C. Vecchi, A. Pietrangelo, and Y. Mizukami Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription Gastroenterology 134 1 2008 226 238
70. A. Pietrangelo Hereditary hemochromatosis: pathogenesis, diagnosis and treatment Gastroenterology 139 2010 393 408
71. J.N. Feder, A. Gnirke, W. Thomas, Z. Tsuchihashi, D.A. Ruddy, and A. Basava A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis Nat Genet 13 4 1996 399 408
72. C. Camaschella, A. Roetto, A. Cali, M. De Gobbi, G. Garozzo, and M. Carella The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22 Nat Genet 25 1 2000 14 15
73. O.T. Njajou, N. Vaessen, M. Joosse, B. Berghuis, J.W. van Dongen, and M.H. Breuning A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis Nat Genet 28 3 2001 213 214
74. A. Roetto, G. Papanikolaou, M. Politou, F. Alberti, D. Girelli, and J. Christakis Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis Nat Genet 33 1 2003 21 22
75. E. Nemeth, A. Roetto, G. Garozzo, T. Ganz, and C. Camaschella Hepcidin is decreased in TFR2 hemochromatosis Blood 105 4 2005 1803 1806
76. A. Kattamis, I. Papassotiriou, D. Palaiologou, F. Apostolakou, A. Galani, and V. Ladis The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major Haematologica 91 6 2006 809 812
77. EASL. EASL Clinical Practice Guidelines on Hemochromatosis. J Hepatol 2010.
78. E. Corradini, P.J. Schmidt, D. Meynard, C. Garuti, G. Montosi, and S. Chen BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice Gastroenterology 2010 10.1053/j.gastro. 2010.07.044
79. S.L. Kearney, E. Nemeth, E.J. Neufeld, D. Thapa, T. Ganz, and D.A. Weinstein Urinary hepcidin in congenital chronic anemias Pediatr Blood Cancer 48 1 2007 57 63
80. G. Weiss Iron metabolism in the anemia of chronic disease Biochim Biophys Acta 1790 7 2009 682 693
81. E. Nemeth Targeting the hepcidin-ferroportin axis in the diagnosis and treatment of anemias Adv Hematol 2010 2010 750643
82. J.L. Babitt, and H.Y. Lin Molecular mechanisms of hepcidin regulation: implications for the anemia of CKD Am J Kidney Dis 55 4 2010 726 741
83. J. Zaritsky, B. Young, H.J. Wang, M. Westerman, G. Olbina, and E. Nemeth Hepcidin-a potential novel biomarker for iron status in chronic kidney disease Clin J Am Soc Nephrol 4 6 2009 1051 1056
84. J. Elliott, D. Mishler, and R. Agarwal Hyporesponsiveness to erythropoietin: causes and management Adv Chronic Kidney Dis 16 2 2009 94 100
85. M.A. Melis, M. Cau, R. Congiu, G. Sole, S. Barella, and A. Cao 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 93 10 2008 1473 1479
86. K.E. Finberg, M.M. Heeney, D.R. Campagna, Y. Aydinok, H.A. Pearson, and K.R. Hartman Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA) Nat Genet 40 5 2008 569 571
87. D.A. Weinstein, C.N. Roy, M.D. Fleming, M.F. Loda, J.I. Wolfsdorf, and N.C. Andrews Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease Blood 100 10 2002 3776 3781
88. A. Chung, K. Leo, G. Wong, K. Chuah, J. Ren, and C. Lee Giant hepatocellular adenoma presenting with chronic iron deficiency anemia Am J Gastroenterol 101 9 2006 2160 2162
89. B.J. Sasu, K.S. Cooke, T.L. Arvedson, C. Plewa, A.R. Ellison, and J. Sheng Anti-hepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia Blood 115 2010 3616 3624
90. M. Hashizume, Y. Uchiyama, N. Horai, N. Tomosugi, and M. Mihara Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production Rheumatol Int 30 7 2010 917 923
91. H. Kawabata, N. Tomosugi, J. Kanda, Y. Tanaka, K. Yoshizaki, and T. Uchiyama Anti-interleukin 6 receptor antibody tocilizumab reduces the level of serum hepcidin in patients with multicentric Castleman's disease Haematologica 92 6 2007 857 858
92. D.R. Ashby, D.P. Gale, M. Busbridge, K.G. Murphy, N.D. Duncan, and T.D. Cairns Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin Haematologica 95 3 2010 505 508
93. H. Huang, M. Constante, A. Layoun, and M.M. Santos Contribution of STAT3 and SMAD4 pathways to the regulation of hepcidin by opposing stimuli Blood 113 15 2009 3593 3599
94. G. Weiss, I. Theurl, S. Eder, C. Koppelstaetter, K. Kurz, and T. Sonnweber Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy Eur J Clin Invest 39 2009 883 890