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Semin Liver Dis 2005; 25(4): 420-432
DOI: 10.1055/s-2005-923314
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Hepatic Iron Metabolism

Gregory J. Anderson1 , 2 , David M. Frazer2
  • 1Head
  • 2Iron Metabolism Laboratory, The Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia
Further Information

Publication History

Publication Date:
29 November 2005 (online)

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ABSTRACT

The liver performs three main functions in iron homeostasis. It is the major site of iron storage, it regulates iron traffic into and around the body through its production of the peptide hepcidin, and it is the site of synthesis of major proteins of iron metabolism such as transferrin and ceruloplasmin. Most of the iron that enters the liver is derived from plasma transferrin under normal circumstances, and transferrin receptors 1 and 2 play important roles in this process. In pathological situations, non-transferrin-bound iron, ferritin, and hemoglobin/haptoglobin and heme/hemopexin complexes assume greater importance in iron delivery to the organ. Iron is stored in the liver as ferritin and, with heavy iron loading, as hemosiderin. The liver can divest itself of iron through the plasma membrane iron exporter ferroportin 1, a process that also requires ceruloplasmin. Hepcidin can regulate this iron release through its interaction with ferroportin.

KEYWORDS

Iron - liver - iron uptake - iron storage - iron release

REFERENCES

  • 1 Finch C. Regulators of iron balance in humans.  Blood. 1994;  84 1697-1702
    CrossrefPubMedGoogle Scholar
  • 2 Bacon B R, Tavill A S. Role of the liver in normal iron metabolism.  Semin Liver Dis. 1984;  4 181-192
    PubMedGoogle Scholar
  • 3 Searle J, Kerr JFR, Halliday J W, Powell L W. Iron storage disease. In: MacSween RNM, Anthony PP, Scheuer PJ, Burt AD, Portmann BC Pathology of the Liver. 3rd ed. London, England; Churchill Livingstone 1994: 219-241
    Google Scholar
  • 4 Van Wyk C P, Linder-Horowitz M, Munro H N. Effect of iron loading on non-heme iron compounds in different liver cell populations.  J Biol Chem. 1971;  246 1025-1031
    PubMedGoogle Scholar
  • 5 Harrison P M, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation.  Biochim Biophys Acta. 1996;  1275 161-203
    CrossrefPubMedGoogle Scholar
  • 6 Ponka P, Beaumont C, Richardson D R. Function and regulation of transferrin and ferritin.  Semin Hematol. 1998;  35 35-54
    PubMedGoogle Scholar
  • 7 Hellman N E, Gitlin J D. Ceruloplasmin metabolism and function.  Annu Rev Nutr. 2002;  22 439-458
    CrossrefPubMedGoogle Scholar
  • 8 Wassell J. Haptoglobin: function and polymorphism.  Clin Lab. 2000;  46 547-552
    PubMedGoogle Scholar
  • 9 Tolosano E, Altruda F. Hemopexin: structure, function, and regulation.  DNA Cell Biol. 2002;  21 297-306
    CrossrefPubMedGoogle Scholar
  • 10 Frazer D M, Anderson G J. The orchestration of body iron intake: how and where do enterocytes receive their cues?.  Blood Cells Mol Dis. 2003;  30 288-297
    CrossrefPubMedGoogle Scholar
  • 11 Ramadori G, Armbrust T. Cytokines in the liver.  Eur J Gastroenterol Hepatol. 2001;  13 777-784
    CrossrefPubMedGoogle Scholar
  • 12 Bastin J M, Jones M, O'Callaghan C A, Schimanski L, Mason D Y, Townsend A R. Kupffer cell staining by an HFE-specific monoclonal antibody: implications for hereditary haemochromatosis.  Br J Haematol. 1998;  103 931-941
    CrossrefPubMedGoogle Scholar
  • 13 Zhang A S, Xiong S, Tsukamoto H, Enns C A. Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes.  Blood. 2004;  103 1509-1514
    CrossrefPubMedGoogle Scholar
  • 14 Montosi G, Corradini E, Garuti C et al.. Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload.  Hepatology. 2005;  41 545-552
    CrossrefPubMedGoogle Scholar
  • 15 Lou D Q, Lesbordes J C, Nicolas G et al.. Iron- and inflammation-induced hepcidin gene expression in mice is not mediated by Kupffer cells in vivo.  Hepatology. 2005;  41 1056-1064
    CrossrefPubMedGoogle Scholar
  • 16 Ramm G A, Britton R S, O'Neill R, Bacon B R. Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes.  J Clin Invest. 1994;  94 9-15
    CrossrefPubMedGoogle Scholar
  • 17 Cairo G. Regulation of liver iron metabolism. In: Templeton DM Molecular and Cellular Iron Transport. New York NY; Marcel Dekker 2001: 613-641
    Google Scholar
  • 18 Lok C N, Loh T T. Regulation of transferrin function and expression: review and update.  Biol Signals Recept. 1998;  7 157-178
    CrossrefPubMedGoogle Scholar
  • 19 Trinder D, Morgan E. Uptake of transferrin-bound iron by mammalian cells. In: Templeton DM Molecular and Cellular Iron Transport. New York NY; Marcel Dekker 2001: 427-449
    Google Scholar
  • 20 Parkes J G, Templeton D M. Transport of non-transferrin-bound iron by hepatocytes. In: Templeton DM Molecular and Cellular Iron Transport. New York NY; Marcel Dekker 2001: 451-466
    Google Scholar
  • 21 Trinder D, Morgan E H, Baker E. The effects of an antibody to the rat transferrin receptor and of rat serum albumin on the uptake of diferric transferrin by rat hepatocytes.  Biochim Biophys Acta. 1988;  943 440-446
    PubMedGoogle Scholar
  • 22 Goldenberg H, Seelos C, Chatwani S, Chegini S, Pumm R. Uptake and endocytic pathway of transferrin and iron in perfused rat liver.  Biochim Biophys Acta. 1991;  1067 145-152
    PubMedGoogle Scholar
  • 23 Morgan E H. Specificity of hepatic iron uptake from plasma transferrin in the rat.  Comp Biochem Physiol A. 1991;  99 91-95
    CrossrefPubMedGoogle Scholar
  • 24 Sciot R, Paterson A C, van den Oord J J, Desmet V J. Lack of hepatic transferrin receptor expression in hemochromatosis.  Hepatology. 1987;  7 831-837
    PubMedGoogle Scholar
  • 25 Lombard M, Bomford A, Hynes M et al.. Regulation of the hepatic transferrin receptor in hereditary hemochromatosis.  Hepatology. 1989;  9 1-5
    PubMedGoogle Scholar
  • 26 Trinder D, Batey R G, Morgan E H, Baker E. Effect of cellular iron concentration on iron uptake by hepatocytes.  Am J Physiol. 1990;  259 G611-G617
    PubMedGoogle Scholar
  • 27 Holmes J M, Morgan E H. Uptake and distribution of transferrin and iron in perfused, iron-deficient rat liver.  Am J Physiol. 1989;  256 G1022-G1027
    PubMedGoogle Scholar
  • 28 Aisen P. Transferrin receptor 1.  Int J Biochem Cell Biol. 2004;  36 2137-2143
    CrossrefPubMedGoogle Scholar
  • 29 Enns C A. The transferrin receptor. In: Templeton DM Molecular and Cellular Iron Transport. New York NY; Marcel Dekker 2001: 71-94
    Google Scholar
  • 30 Watkins J A, Altazan J D, Elder P et al.. Kinetic characterization of reductant dependent processes in iron mobilization from endocytic vesicles.  Biochemistry. 1992;  31 5820-5830
    CrossrefPubMedGoogle Scholar
  • 31 Bali P K, Zak O, Aisen P. A new role for the transferrin receptor in the release of iron from transferrin.  Biochemistry. 1991;  30 324-328
    CrossrefPubMedGoogle Scholar
  • 32 Fleming R E, Sly W S. Mechanisms of iron accumulation in hereditary hemochromatosis.  Annu Rev Physiol. 2002;  64 663-680
    CrossrefPubMedGoogle Scholar
  • 33 Fleming M D, Romano M A, Su M A, Garrick L M, Garrick M D, Andrews N C. 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 1148-1153
    CrossrefPubMedGoogle Scholar
  • 34 Morgan E H, Smith G D, Peters T J. Uptake and subcellular processing of 59Fe-125I-labelled transferrin by rat liver.  Biochem J. 1986;  237 163-173
    PubMedGoogle Scholar
  • 35 Sibille J-C, Octave J-N, Schneider Y-J, Truet A, Crichton R R. Subcellular localization of transferrin protein and iron in the perfused rat liver. Effect of Triton WR 1339, digitonin and temperature.  Eur J Biochem. 1986;  155 47-55
    CrossrefPubMedGoogle Scholar
  • 36 Vogel W, Bomford A, Young S, Williams R. Heterogeneous distribution of transferrin receptors on parenchymal and nonparenchymal liver cells: biochemical and morphological evidence.  Blood. 1987;  69 264-270
    PubMedGoogle Scholar
  • 37 Gatter K C, Brown G, Trowbridge I S, Woolston R E, Mason D Y. Transferrin receptors in human tissues: their distribution and possible clinical relevance.  J Clin Pathol. 1983;  36 539-545
    PubMedGoogle Scholar
  • 38 De Vos R, Sciot R, van Eyken P, Desmet V J. Immunoelectron microscopic localization of hepatic transferrin receptors in human liver with and without iron overload.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;  55 11-17
    PubMedGoogle Scholar
  • 39 Basclain K A, Shiklin K B, Withers G, Reed W D, Jeffrey G P. Cellular expression and regulation of iron transport and storage proteins in genetic haemochromatosis.  J Gastroenterol Hepatol. 1998;  13 624-634
    PubMedGoogle Scholar
  • 40 Tavassoli M, Kishimoto T, Soda R, Kataoka M, Harjes K. Liver endothelium mediates the uptake of iron-transferrin complex by hepatocytes.  Exp Cell Res. 1986;  165 369-379
    CrossrefPubMedGoogle Scholar
  • 41 Bridle K R, Crawford DHG, Ramm G A. Identification and characterization of the hepatic stellate cell transferrin receptor.  Am J Pathol. 2003;  162 1661-1667
    CrossrefPubMedGoogle Scholar
  • 42 Levine D S, Woods J W. Immunolocalization of transferrin and transferrin receptor in mouse small intestinal absorptive cells.  J Histochem Cytochem. 1990;  38 851-858
    PubMedGoogle Scholar
  • 43 Hirose-Kumagai A, Akamatsu N. Change in transferrin receptor distribution in regenerating rat liver.  Biochem Biophys Res Commun. 1989;  164 1105-1112
    CrossrefPubMedGoogle Scholar
  • 44 Eisenstein R S. Iron regulatory proteins and the molecular control of mammalian iron metabolism.  Annu Rev Nutr. 2000;  20 627-662
    CrossrefPubMedGoogle Scholar
  • 45 Lu J P, Hayashi K, Awai M. Transferrin receptor expression in normal, iron-deficient and iron-overloaded rats.  Acta Pathol Jpn. 1989;  39 759-764
    PubMedGoogle Scholar
  • 46 Sciot R, Verhoeven G, Van Eyken P, Cailleau J, Desmet V J. Transferrin receptor expression in rat liver: immunohistochemical and biochemical analysis of the effect of age and iron storage.  Hepatology. 1990;  11 416-427
    PubMedGoogle Scholar
  • 47 Pietrangelo A, Rocchi E, Ferrari A, Ventura E, Cairo G. Regulation of hepatic transferrin, transferrin receptor and ferritin genes in human siderosis.  Hepatology. 1991;  14 1083-1089
    CrossrefPubMedGoogle Scholar
  • 48 Trinder D, Morgan E H, Baker E. The mechanisms of iron uptake by fetal rat hepatocytes in culture.  Hepatology. 1986;  6 852-858
    PubMedGoogle Scholar
  • 49 Tei I, Makino Y, Kadoofuku T, Kanamura I, Konn K. Increase of transferrin receptors in regenerating rat liver cells after partial hepatectomy.  Biochem Biophys Res Commun. 1984;  121 717-721
    CrossrefPubMedGoogle Scholar
  • 50 Trinder D, Zak O, Aisen P. Transferrin receptor-independent uptake of differic transferrin by human hepatoma cells with antisense inhibition of receptor expression.  Hepatology. 1996;  23 1512-1520
    PubMedGoogle Scholar
  • 51 Kawabata H, Yang R, Hirama T et al.. Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.  J Biol Chem. 1999;  274 20826-20832
    CrossrefPubMedGoogle Scholar
  • 52 Lee A W, Oates P S, Trinder D. Effects of cell proliferation on the uptake of transferrin-bound iron by human hepatoma cells.  Hepatology. 2003;  38 967-977
    CrossrefPubMedGoogle Scholar
  • 53 Robb A D, Ericsson M, Wessling-Resnick M. Transferrin receptor 2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies.  Am J Physiol Cell Physiol. 2004;  287 C1769-C1775
    CrossrefPubMedGoogle Scholar
  • 54 Fleming R E, Migas M C, Holden C C et al.. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.  Proc Natl Acad Sci USA. 2000;  97 2214-2219
    CrossrefPubMedGoogle Scholar
  • 55 Deaglio S, Capobianco A, Cali A et al.. Structural, functional, and tissue distribution analysis of human transferrin receptor-2 by murine monoclonal antibodies and polyclonal antiserum.  Blood. 2002;  100 3782-3789
    CrossrefPubMedGoogle Scholar
  • 56 Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin.  Blood. 2004;  104 4294-4299
    CrossrefPubMedGoogle Scholar
  • 57 Johnson M B, Enns C A. Diferric transferrin regulates transferrin receptor 2 protein stability.  Blood. 2004;  104 4287-4293
    CrossrefPubMedGoogle Scholar
  • 58 Camaschella C, Roetto A, Cali A et al.. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.  Nat Genet. 2000;  25 14-15
    CrossrefPubMedGoogle Scholar
  • 59 Fleming R E, Ahmann J R, Migas M C et al.. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.  Proc Natl Acad Sci USA. 2002;  99 10653-10658
    CrossrefPubMedGoogle Scholar
  • 60 Thorstensen K, Romslo I. The role of transferrin in the mechanism of cellular iron uptake.  Biochem J. 1990;  271 1-10
    PubMedGoogle Scholar
  • 61 Cole E S, Glass J. Transferrin binding and iron uptake in mouse hepatocytes.  Biochim Biophys Acta. 1983;  762 102-110
    PubMedGoogle Scholar
  • 62 Thorstensen K, Romslo I. Uptake of iron from transferrin by isolated rat hepatocytes. A redox-mediated plasma membrane process?.  J Biol Chem. 1988;  263 8844-8850
    PubMedGoogle Scholar
  • 63 Trinder D, Morgan E. Inhibition of uptake of transferrin-bound iron by human hepatoma cells by nontransferrin-bound iron.  Hepatology. 1997;  26 691-698
    PubMedGoogle Scholar
  • 64 Graham R M, Morgan E H, Baker E. Ferric citrate uptake by cultured rat hepatocytes is inhibited in the presence of transferrin.  Eur J Biochem. 1998;  253 139-145
    CrossrefPubMedGoogle Scholar
  • 65 Gunshin H, Mackenzie B, Berger U V et al.. Cloning and characterization of a mammalian proton-coupled metal-ion transporter.  Nature. 1997;  388 482-488
    PubMedGoogle Scholar
  • 66 Bowen B J, Morgan E H. Anemia of the Belgrade rat: evidence for defective membrane transport of iron.  Blood. 1987;  70 38-44
    PubMedGoogle Scholar
  • 67 Frazer D M, Vulpe C D, McKie A T et al.. Cloning and gastrointestinal expression of hephaestin: relationship to other iron transport proteins.  Am J Physiol. 2001;  281 G931-G939
    PubMedGoogle Scholar
  • 68 Trinder D, Oates P S, Thomas C, Sadlier J, Morgan E H. Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload.  Gut. 2000;  46 270-276
    CrossrefPubMedGoogle Scholar
  • 69 Tchernitchko D, Bourgeois M, Martin M E, Beaumont C. Expression of the two mRNA isoforms of the iron transporter Nramp2/DMT1 in mice and function of the iron responsive element.  Biochem J. 2002;  363 449-455
    CrossrefPubMedGoogle Scholar
  • 70 Scheiber-Mojdehkar B, Sturm B, Plank L, Kryzer I, Goldenberg H. Influence of parenteral iron preparations on non-transferrin bound iron uptake, the iron regulatory protein and the expression of ferritin and the divalent metal transporter DMT-1 in HepG2 human hepatoma cells.  Biochem Pharmacol. 2003;  65 1973-1978
    CrossrefPubMedGoogle Scholar
  • 71 Hider R C. Nature of nontransferrin-bound iron.  Eur J Clin Invest. 2002;  32(suppl 1) 50-54
    CrossrefPubMedGoogle Scholar
  • 72 Hayashi A, Wada Y, Suzuki T, Shimizu A. Studies on familial hypotransferrinemia: unique clinical course and molecular pathology.  Am J Hum Genet. 1993;  53 201-213
    PubMedGoogle Scholar
  • 73 Bernstein S E. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia.  J Lab Clin Med. 1987;  110 690-705
    PubMedGoogle Scholar
  • 74 Craven C M, Alexander J, Eldridge M, Kushner J P, Bernstein S, Kaplan J. Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis.  Proc Natl Acad Sci USA. 1987;  84 3457-3461
    PubMedGoogle Scholar
  • 75 Wright T L, Brissot P, Ma W-L, Weisinger R A. Characterization of non-transferrin-bound iron clearance by rat liver.  J Biol Chem. 1986;  261 10909-10914
    PubMedGoogle Scholar
  • 76 Randell E W, Parkes J G, Olivieri N F, Templeton D M. Uptake of non-transferrin-bound iron by both reductive and nonreductive processes is modulated by intracellular iron.  J Biol Chem. 1994;  269 16046-16053
    PubMedGoogle Scholar
  • 77 Baker E, Baker S M, Morgan E H. Characterisation of non-transferrin-bound iron (ferric citrate) uptake by rat hepatocytes in culture.  Biochim Biophys Acta. 1998;  1380 21-30
    PubMedGoogle Scholar
  • 78 Gutierrez J A, Yu J, Rivera S, Wessling-Resnick M. Functional expression cloning and characterization of SFT, a stimulator of Fe transport.  J Cell Biol. 1997;  139 895-905
    CrossrefPubMedGoogle Scholar
  • 79 Chua A C, Olynyk J K, Leedman P J, Trinder D. Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis.  Blood. 2004;  104 1519-1525
    CrossrefPubMedGoogle Scholar
  • 80 Yu J, Yu Z K, Wessling-Resnick M. Expression of SFT (stimulator of Fe transport) is enhanced by iron chelation in HeLa cells and by hemochromatosis in liver.  J Biol Chem. 1998;  273 34675-34678
    CrossrefPubMedGoogle Scholar
  • 81 Moestrup S K, Moller H J. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response.  Ann Med. 2004;  36 347-354
    PubMedGoogle Scholar
  • 82 Kristiansen M, Graversen J H, Jacobsen C et al.. Identification of the haemoglobin scavenger receptor.  Nature. 2001;  409 198-201
    PubMedGoogle Scholar
  • 83 Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system.  Crit Rev Biochem Mol Biol. 2003;  38 61-88
    PubMedGoogle Scholar
  • 84 Lim S K, Kim H, Lim S K et al.. Increased susceptibility in Hp knockout mice during acute hemolysis.  Blood. 1998;  92 1870-1877
    PubMedGoogle Scholar
  • 85 Smith A, Farooqui S M, Morgan W T. The murine haemopexin receptor. Evidence that the haemopexin-binding site resides on a 20 kDa subunit and that receptor recycling is regulated by protein kinase C.  Biochem J. 1991;  276 417-425
    PubMedGoogle Scholar
  • 86 Hvidberg V, Maniecki M B, Jacobsen C, Hojrup P, Moller H J, Moestrup S K. Identification of the receptor scavenging hemopexin-heme complexes.  Blood. 2005;  106 2572-2579
    CrossrefPubMedGoogle Scholar
  • 87 Herz J, Strickland D K. LRP: a multifunctional scavenger and signaling receptor.  J Clin Invest. 2001;  108 779-784
    CrossrefPubMedGoogle Scholar
  • 88 Tolosano E, Hirsch E, Patrucco E et al.. Defective recovery and severe renal damage after acute hemolysis in hemopexin-deficient mice.  Blood. 1999;  94 3906-3914
    PubMedGoogle Scholar
  • 89 Halliday J W, Ramm G A, Powell L W. Cellular iron processing and storage: the role of ferritin. In: Brock JH, Halliday JW, Pippard MJ, Powell LW Iron Metabolism in Health and Disease. London, England; WB Saunders 1994: 97-121
    Google Scholar
  • 90 Mack U, Cooksley W G, Ferris R A, Powell L W, Halliday J W. Regulation of plasma ferritin by the isolated perfused rat liver.  Br J Haematol. 1981;  47 403-412
    PubMedGoogle Scholar
  • 91 Moss D, Fargion S, Fracanzani A L et al.. Functional roles of the ferritin receptors of human liver, hepatoma, lymphoid and erythroid cells.  J Inorg Biochem. 1992;  47 219-227
    CrossrefPubMedGoogle Scholar
  • 92 Ramm G A, Powell L W, Halliday J W. Pathways of intracellular trafficking and release of ferritin by the liver in vivo: the effect of chloroquine and cytochalasin D.  Hepatology. 1994;  19 504-513
    CrossrefPubMedGoogle Scholar
  • 93 Sibille J C, Kondo H, Aisen P. Interaction between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein.  Hepatology. 1998;  8 296-301
    PubMedGoogle Scholar
  • 94 Kruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress.  Mutat Res. 2003;  531 81-92
    PubMedGoogle Scholar
  • 95 Arosio P, Levi S. Ferritins: structural and functional aspects. In: Templeton DM Molecular and Cellular Iron Transport. New York NY; Marcel Dekker 2001: 125-154
    Google Scholar
  • 96 Iancu T C. Biological and ultrastructural aspects of iron overload: an overview.  Pediatr Pathol. 1990;  10 281-296
    PubMedGoogle Scholar
  • 97 Iancu T C, Deugnier Y, Halliday J W, Powell L W, Brissot P. Ultrastructural sequences during liver iron overload in genetic hemochromatosis.  J Hepatol. 1997;  27 628-638
    CrossrefPubMedGoogle Scholar
  • 98 Ringeling P L, Cleton M I, Huijskes-Heins M I, Seip M J, de Bruijn W C, van Eijk H G. Analysis of iron-containing compounds in different compartments of the rat liver after iron loading.  Biol Met. 1990;  3 176-182
    PubMedGoogle Scholar
  • 99 Andrews S C, Treffry A, Harrison P M. Siderosomal ferritin. The missing link between ferritin and haemosiderin?.  Biochem J. 1987;  245 439-446
    PubMedGoogle Scholar
  • 100 Miyazaki E, Kato J, Kobune M et al.. Denatured H-ferritin subunit is a major constituent of haemosiderin in the liver of patients with iron overload.  Gut. 2002;  50 413-419
    CrossrefPubMedGoogle Scholar
  • 101 Beguin Y, Huebers H A, Weber G, Eng M, Finch C A. Hepatocyte iron release in rats.  J Lab Clin Med. 1989;  113 346-354
    PubMedGoogle Scholar
  • 102 McKie A T, Marciani P, Rolfs A et al.. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.  Mol Cell. 2000;  5 299-309
    CrossrefPubMedGoogle Scholar
  • 103 Donovan A, Brownlie A, Zhou Y et al.. Postional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter.  Nature. 2000;  403 776-781
    CrossrefPubMedGoogle Scholar
  • 104 Abboud S, Haile D J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism.  J Biol Chem. 2000;  275 19906-19912
    CrossrefPubMedGoogle Scholar
  • 105 Pietrangelo A. Non-HFE hemochromatosis.  Hepatology. 2004;  39 21-29
    CrossrefPubMedGoogle Scholar
  • 106 Donovan A, Lima C A, Pinkus J L et al.. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis.  Cell Metab. 2005;  1 191-200
    CrossrefPubMedGoogle Scholar
  • 107 Xu X, Pin S, Gathinji M, Fuchs R, Harris Z L. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis.  Ann N Y Acad Sci. 2004;  1012 299-305
    CrossrefPubMedGoogle Scholar
  • 108 Harris Z L, Durley A P, Man T K, Gitlin J D. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux.  Proc Natl Acad Sci USA. 1999;  96 10812-10817
    CrossrefPubMedGoogle Scholar
  • 109 Ganz T. Hepcidin-a regulator of intestinal iron absorption and iron recycling by macrophages.  Best Pract Res Clin Haematol. 2005;  18 171-182
    CrossrefPubMedGoogle Scholar
  • 110 Rivera S, Liu L, Nemeth E, Gabayan V, Sorensen O E, Ganz T. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia.  Blood. 2005;  105 1797-1802
    CrossrefPubMedGoogle Scholar
  • 111 Nemeth E, Tuttle M S, Powelson J et al.. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.  Science. 2004;  306 2090-2093
    CrossrefPubMedGoogle Scholar
  • 112 Raedsch R, Stiehl A, Walker S et al.. Biliary excretion of iron in healthy man and in patients with alcoholic cirrhosis of the liver.  Clin Chim Acta. 1990;  193 49-54
    CrossrefPubMedGoogle Scholar
  • 113 Hultcrantz R, Angelin B, Bjorn-Rasmussen E, Ewerth S, Einarsson K. Biliary excretion of iron and ferritin in idiopathic hemochromatosis.  Gastroenterology. 1989;  96 1539-1545
    PubMedGoogle Scholar
  • 114 LeSage G D, Kost L J, Barham S S, LaRusso N F. Biliary excretion of iron from hepatocyte lysosomes in the rat. A major excretory pathway in experimental iron overload.  J Clin Invest. 1986;  77 90-97
    PubMedGoogle Scholar
  • 115 Cleton M I, Sindram J W, Rademakers L H, Zuyderhoudt F M, De Bruijn W C, Marx J J. Ultrastructural evidence for the presence of ferritin-iron in the biliary system of patients with iron overload.  Hepatology. 1986;  6 30-35
    PubMedGoogle Scholar
  • 116 Regoeczi E, Chindemi P A. Translocation of different forms of transferrin from blood to bile in the rat.  Hepatology. 1995;  21 1063-1069
    CrossrefPubMedGoogle Scholar
  • 117 Brissot P, Bolder U, Schteingart C D, Arnaud J, Hofmann A F. Intestinal absorption and enterohepatic cycling of biliary iron originating from plasma non-transferrin-bound iron in rats.  Hepatology. 1997;  25 1457-1461
    CrossrefPubMedGoogle Scholar
  • 118 Pigeon C, Ilyin G, Courselaud B 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 7811-7819
    CrossrefPubMedGoogle Scholar
  • 119 Nicolas G, Bennoun M, Devaux I 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 8780-8785
    CrossrefPubMedGoogle Scholar
  • 120 Millard K N, Frazer D M, Wilkins S J, Anderson G J. Changes in the expression of intestinal iron transport and hepatic regulatory molecules explain the enhanced iron absorption associated with pregnancy in the rat.  Gut. 2004;  53 655-660
    CrossrefPubMedGoogle Scholar
  • 121 Nicolas G, Chauvet C, Viatte L et al.. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation.  J Clin Invest. 2002;  110 1037-1044
    CrossrefPubMedGoogle Scholar
  • 122 Roetto A, Papanikolaou G, Politou M et al.. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.  Nat Genet. 2003;  33 21-22
    CrossrefPubMedGoogle Scholar
  • 123 Feder J N, Gnirke A, Thomas W et al.. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.  Nat Genet. 1996;  13 399-408
    CrossrefPubMedGoogle Scholar
  • 124 Fleming R E, Britton R S, Waheed A, Sly W S, Bacon B R. Pathogenesis of hereditary hemochromatosis.  Clin Liver Dis. 2004;  8 755-773
    CrossrefPubMedGoogle Scholar
  • 125 Ahmad K A, Ahmann J R, Migas M C et al.. Decreased liver hepcidin expression in the Hfe knockout mouse.  Blood Cells Mol Dis. 2002;  29 361-366
    CrossrefPubMedGoogle Scholar
  • 126 Bridle K R, Frazer D M, Wilkins S J et al.. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.  Lancet. 2003;  361 669-673
    CrossrefPubMedGoogle Scholar
  • 127 Batey R G, Lai Chung Fong P, Shamir S, Sherlock S. A non-transferrin-bound serum iron in idiopathic hemochromatosis.  Dig Dis Sci. 1980;  25 340-346
    CrossrefPubMedGoogle Scholar
  • 128 Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis.  Blood. 2005;  105 1803-1806
    CrossrefPubMedGoogle Scholar
  • 129 Papanikolaou G, Samuels M E, Ludwig E H et al.. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.  Nat Genet. 2004;  36 77-82
    CrossrefPubMedGoogle Scholar
  • 130 Niederkofler V, Salie R, Sigrist M, Arber S. Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system.  J Neurosci. 2004;  24 808-818
    CrossrefPubMedGoogle Scholar
  • 131 Samad T A, Rebbapragada A, Bell E et al.. DRAGON, a bone morphogenetic protein co-receptor.  J Biol Chem. 2005;  280 14122-14129
    CrossrefPubMedGoogle Scholar
  • 132 Weinstein D A, Roy C N, Fleming M D, Loda M F, Wolfsdorf J I, Andrews N C. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease.  Blood. 2002;  100 3776-3781
    CrossrefPubMedGoogle Scholar
  • 133 Anderson G J, Frazer D M, Wilkins S J et al.. Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption.  Biochem Soc Trans. 2002;  30 724-726
    PubMedGoogle Scholar
  • 134 Frazer D M, Wilkins S J, Millard K N, McKie A T, Vulpe C D, Anderson G J. Increased hepcidin expression and hypoferraemia associated with an acute phase response are not affected by inactivation of HFE.  Br J Haematol. 2004;  126 434-436
    CrossrefPubMedGoogle Scholar
  • 135 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 9263-9265
    CrossrefPubMedGoogle Scholar
  • 136 Roy C N, Custodio A O, de Graaf J et al.. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice.  Nat Genet. 2004;  36 481-485
    PubMedGoogle Scholar

Gregory J AndersonPh.D. 

Iron Metabolism Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia

Email: Greg.Anderson@qimr.edu.au

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