The Regulation of Cellular Iron Metabolism

REFERENCES

• Neilands J B. Iron and its role in microbial physiology. Microbial Iron Metabolism: A Comprehensive Treatise, J B Neilands. Academic Press, London 1974; 3–34
   Google Scholar
• Stubbe J. Ribonucleotide reductases. Adv Enzymol Relat Areas Mol Biol 1990; 63: 349–419
   PubMedGoogle Scholar
• Baynes R D. Iron deficiency. Iron Metabolism in Health and Disease, J H Brock, J W Halliday, M J Pippard, L W Powell. W. B. Saunders Company Ltd., London 1994; 189–225
   Google Scholar
• Feder J N, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996; 13: 399–408
   PubMed Web of Science ®Google Scholar
• Gunshin H, Mackenzie B, Berger U V, Gunshin Y, Romero M F, Boron W F, Nussberger S, Gollan J L, Hediger M A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997; 388: 482–488
   PubMed Web of Science ®Google Scholar
• Vulpe C D, Kuo Y M, Murphy T L, Cowley L, Askwith C, Libina N, Gitschier J, Anderson G J. Hephestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 1999; 21: 195–199
   PubMed Web of Science ®Google Scholar
• Kawabata H, Yang R, Hirama T, Vuong P T, Kawano S, Gombart A F, Koeffler H P. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 1999; 274: 20826–20832
   PubMed Web of Science ®Google Scholar
• Abboud S, Haile D J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000; 275: 19906–19912
   PubMed Web of Science ®Google Scholar
• Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt S J, Moynihan J, Paw B H, Drejer A, Barut B, Zapata A, Law T C, Brugnara C, Lux S E, Pinkus G S, Pinkus J L, Kingsley P D, Palis J, Fleming M D, Andrews N C, Zon L I. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000; 403: 776–781
   PubMed Web of Science ®Google Scholar
• McKie A T, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters T J, Farzaneh F, Hediger M A, Hentze M W, Simpson R J. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000; 5: 299–309
   PubMed Web of Science ®Google Scholar
• Krause A, Neitz S, Magert H J, Schulz A, Forssmann W G, Schulz-Knappe P, Adermann K. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480: 147–150
   PubMed Web of Science ®Google Scholar
• Park C H, Valore E V, Waring A J, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: 7806–7810
   PubMed Web of Science ®Google Scholar
• McKie A T, Barrow D, Latunde-Dada G O, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters T J, Raja K B, Shirali S, Hediger M A, Farzaneh F, Simpson R J. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001; 291: 1755–1759
   PubMed Web of Science ®Google Scholar
• Papanikolaou G, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004; 36: 77–82
   PubMed Web of Science ®Google Scholar
• Shayeghi M, Latunde-Dada G O, Oakhill J S, Laftah A H, Takeuchi K, Halliday N, Khan Y, Warley A, McCann F E, Hider R C, Frazer D M, Anderson G J, Vulpe C D, Simpson R J, McKie A T. Identification of an intestinal heme transporter. Cell 2005; 122: 789–801
   PubMed Web of Science ®Google Scholar
• Andrews N C. Disorders of iron metabolism. N Engl J Med 1999; 341: 1986–1995
   PubMed Web of Science ®Google Scholar
• Lieu P T, Heiskala M, Peterson P A, Yang Y. The roles of iron in health and disease. Mol Aspects Med 2001; 22: 1–87
   PubMedGoogle Scholar
• Halliwell B, Gutteridge J M. Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch Biochem Biophys 1986; 246: 501–514
   PubMed Web of Science ®Google Scholar
• Aruoma O I, Halliwell B, Laughton M J, Quinlan G J, Gutteridge J M. The mechanism of initiation of lipid peroxidation. Evidence against a requirement for an iron(II)-iron(III) complex. Biochem J 1989; 258: 617–620
   PubMed Web of Science ®Google Scholar
• Conrad M E, Umbreit J N, Moore E G. Iron absorption and transport. Am J Med Sci 1999; 318: 213–219
   PubMed Web of Science ®Google Scholar
• Carpenter C E, Mahoney A W. Contributions of heme and nonheme iron to human nutrition. Crit Rev Food Sci Nutr 1992; 31: 333–367
   PubMed Web of Science ®Google Scholar
• Siah C W, Trinder D, Olynyk J K. Iron overload. Clin Chim Acta 2005; 358: 24–36
   PubMedGoogle Scholar
• Forth W, Rummel W. Iron absorption. Physiol Rev 1973; 53: 724–792
   PubMed Web of Science ®Google Scholar
• Peters T J, Raja K B, Simpson R J, Snape S. Mechanisms and regulation of intestinal iron absorption. Ann NY Acad Sci 1988; 526: 141–147
   PubMed Web of Science ®Google Scholar
• Conrad M E, Weintraub L R, Sears D A, Crosby W H. Absorption of hemoglobin iron. Am J Physiol 1966; 211: 1123–1130
   PubMedGoogle Scholar
• Wheby M S, Suttle G E, Ford K T, 3rd. Intestinal absorption of hemoglobin iron. Gastroenterology 1970; 58: 647–654
   PubMed Web of Science ®Google Scholar
• Grasbeck R, Kouvonen I, Lundberg M, Tenhunen R. An intestinal receptor for heme. Scand J Haematol 1979; 23: 5–9
   PubMedGoogle Scholar
• Grasbeck R, Majuri R, Kouvonen I, Tenhunen R. Spectral and other studies on the intestinal haem receptor of the pig. Biochim Biophys Acta 1982; 700: 137–142
   PubMedGoogle Scholar
• Raffin S B, Woo C H, Roost K T, Price D C, Schmid R. Intestinal absorption of hemoglobin iron-heme cleavage by mucosal heme oxygenase. J Clin Invest 1974; 54: 1344–1352
   PubMed Web of Science ®Google Scholar
• Levine D S, Huebers H A, Rubin C E, Finch C A. Blocking action of parenteral desferrioxamine on iron absorption in rodents and men. Gastroenterology 1988; 95: 1242–1248
   PubMed Web of Science ®Google Scholar
• Quigley J G, Yang Z, Worthington M T, Phillips J D, Sabo K M, Sabath D E, Berg C L, Sassa S, Wood B L, Abkowitz J L. Identification of a human heme exporter that is essential for erythropoiesis. Cell 2004; 118: 757–766
   PubMed Web of Science ®Google Scholar
• Raja K B, Simpson R J, Peters T J. Investigation of a role for reduction in ferric iron uptake by mouse duodenum. Biochim Biophys Acta 1992; 1135: 141–146
   PubMed Web of Science ®Google Scholar
• Riedel H D, Remus A J, Fitscher B A, Stremmel W. Characterization and partial purification of a ferrireductase from human duodenal microvillus membranes. Biochem J 1995; 309: 745–748
   PubMed Web of Science ®Google Scholar
• Gunshin H, Starr C N, Direnzo C, Fleming M D, Jin J, Greer E L, Sellers V M, Galica S M, Andrews N C. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood 2005; 106: 2879–2883
   PubMed Web of Science ®Google Scholar
• Ohgami R S, Campagna D R, McDonald A, Fleming M D. The Steap proteins are metalloreductases. Blood 2006; 108: 1388–1394
   PubMed Web of Science ®Google Scholar
• Fleming M D, Trenor C C, 3rd, Su M A, Foernzler D, Beier D R, Dietrich W F, Andrews N C. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 1997; 16: 383–386
   PubMed Web of Science ®Google Scholar
• Tandy S, Williams M, Leggett A, Lopez-Jimenez M, Dedes M, Ramesh B, Srai S K, Sharp P. Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. J Biol Chem 2000; 275: 1023–1029
   PubMed Web of Science ®Google Scholar
• Brittenham G M. The red cell cycle. Iron Metabolism in Health and Disease, J H Brock, J W Halliday, M J Pippard, L W Powell. W. B. Saunders Company Ltd., London 1994; 31–62
   Google Scholar
• Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr 2006; 26: 323–342
   PubMed Web of Science ®Google Scholar
• Donovan A, Lima C A, Pinkus J L, Pinkus G S, Zon L I, Robine S, Andrews N C. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 2005; 1: 191–200
   PubMed Web of Science ®Google Scholar
• Hemmaplardh D, Morgan E H. The role of endocytosis in transferrin uptake by reticulocytes and bone marrow cells. Br J Haematol 1977; 36: 85–96
   PubMed Web of Science ®Google Scholar
• Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002; 99: 4596–4601
   PubMed Web of Science ®Google Scholar
• Frazer D M, Inglis H R, Wilkins S J, Millard K N, Steele T M, McLaren G D, McKie A T, Vulpe C D, Anderson G J. Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut 2004; 53: 1509–1515
   PubMed Web of Science ®Google Scholar
• Enns C A, Shindelman J E, Tonik S E, Sussman H H. Radioimmunochemical measurement of the transferrin receptor in human trophoblast and reticulocyte membranes with a specific anti-receptor antibody. Proc Natl Acad Sci USA 1981; 78: 4222–4225
   PubMed Web of Science ®Google Scholar
• Young S P, Roberts S, Bomford A. Intracellular processing of transferrin and iron by isolated rat hepatocytes. Biochem J 1985; 232: 819–823
   PubMedGoogle Scholar
• Pollack S, Campana T. Low molecular weight nonheme iron and a highly labeled heme pool in the reticulocyte. Blood 1980; 56: 564–566
   Google Scholar
• Mulligan M, Althaus B, Linder M C. Non-ferritin, non-heme iron pools in rat tissues. Int J Biochem 1986; 18: 791–798
   PubMedGoogle Scholar
• Jacobs A. Low molecular weight intracellular iron transport compounds. Blood 1977; 50: 433–439
   PubMed Web of Science ®Google Scholar
• Pollack S. Intracellular iron. Adv Exp Med Biol 1994; 356: 165–171
   Google Scholar
• Harrison P M. Ferritin: an iron-storage molecule. Semin Hematol 1977; 14: 55–70
   PubMed Web of Science ®Google Scholar
• Harrison P M, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta 1996; 1275: 161–203
   PubMed Web of Science ®Google Scholar
• Adelman T G, Arosio P, Drysdale J W. Multiple subunits in human ferritins: evidence for hybrid molecules. Biochem Biophys Res Commun 1975; 63: 1056–1062
   PubMedGoogle Scholar
• Bomford A, Conlon-Hollingshead C, Munro H N. Adaptive responses of rat tissue isoferritins to iron administration. Changes in subunit synthesis, isoferritin abundance, and capacity for iron storage. J Biol Chem 1981; 256: 948–955
   PubMed Web of Science ®Google Scholar
• Halliday J W, Ramm G A, Powell L W. Cellular iron processing and storage: The role of ferritin. Iron Metabolism in Health and Disease, J H Brock, J W Halliday, M J Pippard, L W Powell. W. B. Saunders Company Ltd., London 1994; 97–121
   Google Scholar
• Ke Y, Wu J, Leibold E A, Walden W E, Theil E C. Loops and bulge/loops in iron-responsive element isoforms influence iron regulatory protein binding. Fine-tuning of mRNA regulation?. J Biol Chem 1998; 273: 23637–23640
   PubMedGoogle Scholar
• Wei Y, Miller S C, Tsuji Y, Torti S V, Torti F M. Interleukin 1 induces ferritin heavy chain in human muscle cells. Biochem Biophys Res Commun 1990; 169: 289–296
   PubMed Web of Science ®Google Scholar
• Fahmy M, Young S P. Modulation of iron metabolism in monocyte cell line U937 by inflammatory cytokines: changes in transferrin uptake, iron handling and ferritin mRNA. Biochem J 1993; 296: 175–181
   PubMed Web of Science ®Google Scholar
• Chasteen N D, Harrison P M. Mineralization in ferritin: an efficient means of iron storage. J Struct Biol 1999; 126: 182–194
   PubMed Web of Science ®Google Scholar
• Reilly C A, Aust S D. Iron loading into ferritin by an intracellular ferroxidase. Arch Biochem Biophys 1998; 359: 69–76
   Google Scholar
• Rudeck M, Volk T, Sitte N, Grune T. Ferritin oxidation in vitro: implication of iron release and degradation by the 20S proteasome. IUBMB Life 2000; 49: 451–456
   PubMed Web of Science ®Google Scholar
• De Domenico I, Vaughn M B, Li L, Bagley D, Musci G, Ward D M, Kaplan J. Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J 2006; 25: 5396–5404
   PubMed Web of Science ®Google Scholar
• Munro H N, Linder M C. Ferritin: structure, biosynthesis, and role in iron metabolism. Physiol Rev 1978; 58: 317–396
   PubMed Web of Science ®Google Scholar
• Richter G W. Studies of iron overload. Lysosomal proteolysis of rat liver ferritin. Pathol Res Pract 1986; 181: 159–167
   Google Scholar
• Finch S C, Finch C A. Idiopathic hemochromatosis, an iron storage disease. A. Iron metabolism in hemochromatosis. Medicine (Baltimore) 1955; 34: 381–430
   PubMed Web of Science ®Google Scholar
• Kaldor I. Studies on intermediary iron metabolism. XII. Measurement of the iron derived from water soluble and water insoluble non-haem compounds (ferritin and haemosiderin iron) in liver and spleen. Aust J Exp Biol Med Sci 1958; 36: 173–182
   Google Scholar
• Millar J A, Cumming R L, Smith J A, Goldberg A. Effect of actinomycin D, cycloheximide, and acute blood loss of ferritin synthesis in rat liver. Biochem J 1970; 119: 643–649
   PubMed Web of Science ®Google Scholar
• Wyllie J C, Kaufman N. A study of storage iron in the pregnant rat. Br J Haematol 1971; 20: 321–327
   PubMed Web of Science ®Google Scholar
• O'Connell M, Halliwell B, Moorhouse C P, Aruoma O I, Baum H, Peters T J. Formation of hydroxyl radicals in the presence of ferritin and haemosiderin. Is haemosiderin formation a biological protective mechanism?. Biochem J 1986; 234: 727–731
   PubMed Web of Science ®Google Scholar
• Green R, Charlton R, Seftel H, Bothwell T, Mayet F, Adams B, Finch C, Layrisse M. Body iron excretion in man: a collaborative study. Am J Med 1968; 45: 336–353
   PubMed Web of Science ®Google Scholar
• Miret S, Simpson R J, McKie A T. Physiology and molecular biology of dietary iron absorption. Annu Rev Nutr 2003; 23: 283–301
   PubMed Web of Science ®Google Scholar
• Hallberg L, Hogdahl A M, Nilsson L, Rybo G. Menstrual blood loss—a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966; 45: 320–351
   PubMed Web of Science ®Google Scholar
• Hallberg L. Perspectives on nutritional iron deficiency. Annu Rev Nutr 2001; 21: 1–21
   PubMed Web of Science ®Google Scholar
• Brune M, Magnusson B, Persson H, Hallberg L. Iron losses in sweat. Am J Clin Nutr 1986; 43: 438–443
   PubMed Web of Science ®Google Scholar
• Morgan E H. Iron metabolism and transport. Hepatology: A Textbook of Liver Disease, D Zakim, T D Boyer. W. B. Saunders Company Ltd., New York 1996; 526–554
   Google Scholar
• Morgan E H. Transferrin biochemistry, physiology and clinical significance. Molec Aspects Med 1981; 4: 1–123
   Web of Science ®Google Scholar
• Jordan S M, Morgan E H. Plasma protein synthesis by tissue slices from pregnant and lactating rats. Biochim Biophys Acta 1969; 174: 373–379
   Google Scholar
• Takeda A, Devenyi A, Connor J R. Evidence for non-transferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice. J Neurosci Res 1998; 51: 454–462
   Google Scholar
• Anderson B F, Baker H M, Dodson E J, Norris G E, Rumball S V, Waters J M, Baker E N. Structure of human lactoferrin at 3.2-A resolution. Proc Natl Acad Sci USA 1987; 84: 1769–1773
   PubMed Web of Science ®Google Scholar
• Bailey S, Evans R W, Garratt R C, Gorinsky B, Hasnain S, Horsburgh C, Jhoti H, Lindley P F, Mydin A, Sarra R, et al. Molecular structure of serum transferrin at 3.3-A resolution. Biochemistry 1988; 27: 5804–5812
   PubMed Web of Science ®Google Scholar
• Cheng Y, Zak O, Aisen P, Harrison S C, Walz T. Structure of the human transferrin receptor-transferrin complex. Cell 2004; 116: 565–576
   PubMed Web of Science ®Google Scholar
• Yang F, Lum J B, McGill J R, Moore C M, Naylor S L, van Bragt P H, Baldwin W D, Bowman B H. Human transferrin: cDNA characterization and chromosomal localization. Proc Natl Acad Sci USA 1984; 81: 2752–2756
   PubMed Web of Science ®Google Scholar
• Aisen P, Aasa R, Redfield A G. The chromium, manganese, and cobalt complexes of transferrin. J Biol Chem 1969; 244: 4628–4633
   PubMed Web of Science ®Google Scholar
• Davidsson L, Lonnerdal B, Sandstrom B, Kunz C, Keen C L. Identification of transferrin as the major plasma carrier protein for manganese introduced orally or intravenously or after in vitro addition in the rat. J Nutr 1989; 119: 1461–1464
   PubMed Web of Science ®Google Scholar
• Baker E N, Lindley P F. New perspectives on the structure and function of transferrins. J Inorg Biochem 1992; 47: 147–160
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Bali P K, Aisen P. Receptor-modulated iron release from transferrin: differential effects on N- and C-terminal sites. Biochemistry 1991; 30: 9947–9952
   Google Scholar
• Aisen P, Leibman A, Zweier J. Stoichiometric and site characteristics of the binding of iron to human transferrin. J Biol Chem 1978; 253: 1930–1937
   PubMed Web of Science ®Google Scholar
• Jandl J H, Katz J H. The plasma-to-cell cycle of transferrin. J Clin Invest 1963; 42: 314–326
   PubMed Web of Science ®Google Scholar
• McClelland A, Kuhn L C, Ruddle F H. The human transferrin receptor gene: genomic organization, and the complete primary structure of the receptor deduced from a cDNA sequence. Cell 1984; 39: 267–274
   PubMed Web of Science ®Google Scholar
• Evans P, Kemp J. Exon/intron structure of the human transferrin receptor gene. Gene 1997; 199: 123–131
   Google Scholar
• Jing S Q, Trowbridge I S. Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid-attachment site. EMBO J 1987; 6: 327–331
   PubMed Web of Science ®Google Scholar
• Schneider C, Sutherland R, Newman R, Greaves M. Structural features of the cell surface receptor for transferrin that is recognized by the monoclonal antibody OKT9. J Biol Chem 1982; 257: 8516–8522
   PubMed Web of Science ®Google Scholar
• Schneider C, Owen M J, Banville D, Williams J G. Primary structure of human transferrin receptor deduced from the mRNA sequence. Nature 1984; 311: 675–678
   PubMed Web of Science ®Google Scholar
• Enns C A, Sussman H H. Physical characterization of the transferrin receptor in human placentae. J Biol Chem 1981; 256: 9820–9823
   Google Scholar
• Sheth S, Brittenham G M. Genetic disorders affecting proteins of iron metabolism: clinical implications. Annu Rev Med 2000; 51: 443–464
   Google Scholar
• Lawrence C M, Ray S, Babyonyshev M, Galluser R, Borhani D W, Harrison S C. Crystal structure of the ectodomain of human transferrin receptor. Science 1999; 286: 779–782
   PubMed Web of Science ®Google Scholar
• Dautry-Varsat A, Ciechanover A, Lodish H F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc Natl Acad Sci USA 1983; 80: 2258–2262
   PubMed Web of Science ®Google Scholar
• Young S P, Bomford A, Williams R. The effect of the iron saturation of transferrin on its binding and uptake by rabbit reticulocytes. Biochem J 1984; 219: 505–510
   PubMed Web of Science ®Google Scholar
• Tsunoo H, Sussman H H. Characterization of transferrin binding and specificity of the placental transferrin receptor. Arch Biochem Biophys 1983; 225: 42–54
   Google Scholar
• Davies M, Parry J E, Sutcliffe R G. Examination of different preparations of human placental plasma membrane for the binding of insulin, transferrin and immunoglobulins. J Reprod Fertil 1981; 63: 315–324
   Google Scholar
• Enns C A, Suomalainen H A, Gebhardt J E, Schroder J, Sussman H H. Human transferrin receptor: expression of the receptor is assigned to chromosome 3. Proc Natl Acad Sci USA 1982; 79: 3241–3245
   PubMed Web of Science ®Google Scholar
• Ponka P, Lok C N. The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 1999; 31: 1111–1137
   PubMed Web of Science ®Google Scholar
• Casey J L, Hentze M W, Koeller D M, Caughman S W, Rouault T A, Klausner R D, Harford J B. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science 1988; 240: 924–928
   PubMed Web of Science ®Google Scholar
• Hentze M W, Caughman S W, Casey J L, Koeller D M, Rouault T A, Harford J B, Klausner R D. A model for the structure and functions of iron-responsive elements. Gene 1988; 72: 201–208
   PubMed Web of Science ®Google Scholar
• Cairo G, Pietrangelo A. Nitric-oxide-mediated activation of iron-regulatory protein controls hepatic iron metabolism during acute inflammation. Eur J Biochem 1995; 232: 358–363
   PubMedGoogle Scholar
• Lok C N, Ponka P. Identification of an erythroid active element in the transferrin receptor gene. J Biol Chem 2000; 275: 24185–24190
   Google Scholar
• Paterson S, Armstrong N J, Iacopetta B J, McArdle H J, Morgan E H. Intravesicular pH and iron uptake by immature erythroid cells. J Cell Physiol 1984; 120: 225–232
   Google Scholar
• Su M A, Trenor C C, Fleming J C, Fleming M D, Andrews N C. The G185R mutation disrupts function of the iron transporter Nramp2. Blood 1998; 92: 2157–2163
   PubMed Web of Science ®Google Scholar
• Morgan E H. Effect of pH and iron content of transferrin on its binding to reticulocyte receptors. Biochim Biophys Acta 1983; 762: 498–502
   PubMed Web of Science ®Google Scholar
• Qian Z M, Morgan E H. Changes in the uptake of transferrin-free and transferrin-bound iron during reticulocyte maturation in vivo and in vitro. Biochim Biophys Acta 1992; 1135: 35–43
   Google Scholar
• Morgan E H, Baker E. Iron uptake and metabolism by hepatocytes. Fed Proc 1986; 45: 2810–2816
   PubMedGoogle Scholar
• Morgan E H. Inhibition of reticulocyte iron uptake by NH4Cl and CH3NH2. Biochim Biophys Acta 1981; 642: 119–134
   Google Scholar
• Ohgami R S, Campagna D R, Greer E L, Antiochos B, McDonald A, Chen J, Sharp J J, Fujiwara Y, Barker J E, Fleming M D. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet 2005; 37: 1264–1269
   PubMed Web of Science ®Google Scholar
• Gruenheid S, Canonne-Hergaux F, Gauthier S, Hackam D J, Grinstein S, Gros P. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J Exp Med 1999; 189: 831–841
   PubMed Web of Science ®Google Scholar
• Bowen B J, Morgan E H. Anemia of the Belgrade rat: evidence for defective membrane transport of iron. Blood 1987; 70: 38–44
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Edwards J A, Hoke J E. Red cell iron uptake in hereditary microcytic anemia. Blood 1975; 46: 381–388
   Google Scholar
• Edwards J A, Garrick L M, Hoke J E. Defective iron uptake and globin synthesis by erythroid cells in the anemia of the Belgrade laboratory rat. Blood 1978; 51: 347–357
   PubMed Web of Science ®Google Scholar
• Parkkila S, Waheed A, Britton R S, Bacon B R, Zhou X Y, Tomatsu S, Fleming R E, Sly W S. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA 1997; 94: 13198–13202
   PubMed Web of Science ®Google Scholar
• Feder J N, Penny D M, Irrinki A, Lee V K, Lebron J A, Watson N, Tsuchihashi Z, Sigal E, Bjorkman P J, Schatzman R C. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 1998; 95: 1472–1477
   PubMed Web of Science ®Google Scholar
• Lebron J A, West A P, Jr., Bjorkman P J. The hemochromatosis protein HFE competes with transferrin for binding to the transferrin receptor. J Mol Biol 1999; 294: 239–245
   PubMed Web of Science ®Google Scholar
• Fleming R E, Migas M C, Holden C C, Waheed A, Britton R S, Tomatsu S, Bacon B R, Sly W S. 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
   PubMed Web of Science ®Google Scholar
• Kawabata H, Nakamaki T, Ikonomi P, Smith R D, Germain R S, Koeffler H P. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 2001; 98: 2714–2719
   PubMed Web of Science ®Google Scholar
• Merle U, Theilig F, Fein E, Gehrke S, Kallinowski B, Riedel H D, Bachmann S, Stremmel W, Kulaksiz H. Localization of the iron-regulatory proteins hemojuvelin and transferrin receptor 2 to the basolateral membrane domain of hepatocytes. Histochem Cell Biol 2007; 127: 221–226
   Google Scholar
• Calzolari A, Deaglio S, Sposi N M, Petrucci E, Morsilli O, Gabbianelli M, Malavasi F, Peschle C, Testa U. Transferrin receptor 2 protein is not expressed in normal erythroid cells. Biochem J 2004; 381: 629–634
   PubMedGoogle Scholar
• Levy J E, Jin O, Fujiwara Y, Kuo F, Andrews N C. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 1999; 21: 396–399
   PubMed Web of Science ®Google Scholar
• Kawabata H, Germain R S, Vuong P T, Nakamaki T, Said J W, Koeffler H P. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 2000; 275: 16618–16625
   PubMed Web of Science ®Google Scholar
• West A P, Jr., Bennett M J, Sellers V M, Andrews N C, Enns C A, Bjorkman P J. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem 2000; 275: 38135–38138
   PubMed Web of Science ®Google Scholar
• 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
   Google Scholar
• Griffiths W J, Cox T M. 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: 613–624
   Google Scholar
• Goswami T, Andrews N C. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006; 281: 28494–28498
   PubMed Web of Science ®Google Scholar
• Cole E S, Glass J. Transferrin binding and iron uptake in mouse hepatocytes. Biochim Biophys Acta 1983; 762: 102–110
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   Google Scholar
• Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood 2004; 104: 4294–4299
   PubMed Web of Science ®Google Scholar
• Johnson M B, Enns C A. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood 2004; 104: 4287–4293
   PubMed Web of Science ®Google Scholar
• Warren G, Davoust J, Cockcroft A. Recycling of transferrin receptors in A431 cells is inhibited during mitosis. EMBO J 1984; 3: 2217–2225
   PubMed Web of Science ®Google Scholar
• Gruenheid S, Cellier M, Vidal S, Gros P. Identification and characterization of a second mouse Nramp gene. Genomics 1995; 25: 514–525
   PubMed Web of Science ®Google Scholar
• Lee P L, Gelbart T, West C, Halloran C, Beutler E. The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis 1998; 24: 199–215
   PubMed Web of Science ®Google Scholar
• Hubert N, Hentze M W. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci USA 2002; 99: 12345–12350
   PubMed Web of Science ®Google Scholar
• Gunshin H, Allerson C R, Polycarpou-Schwarz M, Rofts A, Rogers J T, Kishi F, Hentze M W, Rouault T A, Andrews N C, Hediger M A. Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett 2001; 509: 309–316
   PubMed Web of Science ®Google Scholar
• Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 1999; 93: 4406–4417
   PubMed Web of Science ®Google Scholar
• Trinder D, Oates P S, Thomas C, Sadleir 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
   PubMed Web of Science ®Google Scholar
• Touret N, Furuya W, Forbes J, Gros P, Grinstein S. Dynamic traffic through the recycling compartment couples the metal transporter Nramp2 (DMT1) with the transferrin receptor. J Biol Chem 2003; 278: 25548–25557
   PubMed Web of Science ®Google Scholar
• Picard V, Govoni G, Jabado N, Gros P. Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. J Biol Chem 2000; 275: 35738–35745
   PubMed Web of Science ®Google Scholar
• Edwards J A, Hoke J E. Defect of intestinal mucosal iron uptake in mice with hereditary microcytic anemia. Proc Soc Exp Biol Med 1972; 141: 81–84
   PubMed Web of Science ®Google Scholar
• Fleming M D, Andrews N C. Mammalian iron transport: an unexpected link between metal homeostasis and host defense. J Lab Clin Med 1998; 132: 464–468
   PubMedGoogle Scholar
• Zoller H, Pietrangelo A, Vogel W, Weiss G. Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet 1999; 353: 2120–2123
   PubMed Web of Science ®Google Scholar
• Zhou X Y, Tomatsu S, Fleming R E, Parkkila S, Waheed A, Jiang J, Fei Y, Brunt E M, Ruddy D A, Prass C E, Schatzman R C, O'Neill R, Britton R S, Bacon B R, Sly W S. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 1998; 95: 2492–2497
   PubMed Web of Science ®Google Scholar
• Fleming R E, Migas M C, Zhou X, Jiang J, Britton R S, Brunt E M, Tomatsu S, Waheed A, Bacon B R, Sly W S. Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci USA 1999; 96: 3143–3148
   PubMed Web of Science ®Google Scholar
• Chua A CG, 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
   PubMed Web of Science ®Google Scholar
• Liu X B, Hill P, Haile D J. Role of the ferroportin iron-responsive element in iron and nitric oxide dependent gene regulation. Blood Cells Mol Dis 2002; 29: 315–326
   Google Scholar
• Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile D J, Pietrangelo A. The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression. J Hepatol 2003; 39: 710–715
   PubMed Web of Science ®Google Scholar
• Yang F, Liu X B, Quinones M, Melby P C, Ghio A, Haile D J. Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation. J Biol Chem 2002; 277: 39786–39791
   PubMed Web of Science ®Google Scholar
• Nemeth E, Tuttle M S, Powelson J, Vaughn M B, Donovan A, Ward D M, Ganz T, Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090–2093
   PubMed Web of Science ®Google Scholar
• Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, Trenor C C, Gasparini P, Andrews N C, Pietrangelo A. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 2001; 108: 619–623
   PubMed Web of Science ®Google Scholar
• Njajou O T, Vaessen N, Joosse M, Berghuis B, van Dongen J W, Breuning M H, Snijders P J, Rutten W P, Sandkuijl L A, Oostra B A, van Duijn C M, Heutink P. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001; 28: 213–214
   PubMed Web of Science ®Google Scholar
• Devalia V, Carter K, Walker A P, Perkins S J, Worwood M, May A, Dooley J S. Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 2002; 100: 695–697
   PubMed Web of Science ®Google Scholar
• Hellman N E, Gitlin J D. Ceruloplasmin metabolism and function. Annu Rev Nutr 2002; 22: 439–458
   PubMed Web of Science ®Google Scholar
• Miyajima H, Nishimura Y, Mizoguchi K, Sakamoto M, Shimizu T, Honda N. Familial apoceruloplasmin deficiency associated with blepharospasm and retinal degeneration. Neurology 1987; 37: 761–767
   PubMed Web of Science ®Google Scholar
• Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Morita H, Hiyamuta S, Ikeda S, Shimizu N, Yanagisawa N. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 1995; 9: 267–272
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Daimon M, Yamatani K, Igarashi M, Fukase N, Kawanami T, Kato T, Tominaga M, Sasaki H. Fine structure of the human ceruloplasmin gene. Biochem Biophys Res Commun 1995; 208: 1028–1035
   PubMedGoogle Scholar
• Yang F, Naylor S L, Lum J B, Cutshaw S, McCombs J L, Naberhaus K H, McGill J R, Adrian G S, Moore C M, Barnett D R, Bowman B H. Characterization, mapping, and expression of the human ceruloplasmin gene. Proc Natl Acad Sci USA 1986; 83: 3257–3261
   PubMed Web of Science ®Google Scholar
• Koschinsky M L, Funk W D, van Oost B A, MacGillivray R T. Complete cDNA sequence of human preceruloplasmin. Proc Natl Acad Sci USA 1986; 83: 5086–5090
   PubMed Web of Science ®Google Scholar
• Aldred A R, Grimes A, Schreiber G, Mercer J F. Rat ceruloplasmin. Molecular cloning and gene expression in liver, choroid plexus, yolk sac, placenta, and testis. J Biol Chem 1987; 262: 2875–2878
   PubMed Web of Science ®Google Scholar
• Klomp L W, Gitlin J D. Expression of the ceruloplasmin gene in the human retina and brain: implications for a pathogenic model in aceruloplasminemia. Hum Mol Genet 1996; 5: 1989–1996
   PubMed Web of Science ®Google Scholar
• Yang F, Friedrichs W E, deGraffenried L, Herbert D C, Weaker F J, Bowman B H, Coalson J J. Cellular expression of ceruloplasmin in baboon and mouse lung during development and inflammation. Am J Respir Cell Mol Biol 1996; 14: 161–169
   PubMed Web of Science ®Google Scholar
• Osaki S, Johnson D A, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 1966; 241: 2746–2751
   PubMed Web of Science ®Google Scholar
• Hershko C, Cook J D, Finch D A. Storage iron kinetics. 3. Study of desferrioxamine action by selective radioiron labels of RE and parenchymal cells. J Lab Clin Med 1973; 81: 876–886
   PubMedGoogle Scholar
• Sibille J C, Octave J N, Schneider Y J, Trouet A, Crichton 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
   Google Scholar
• Grohlich D, Morley C G, Miller R J, Bezkorovainy A. Iron incorporation into isolated rat hepatocytes. Biochem Biophys Res Commun 1977; 76: 682–690
   PubMed Web of Science ®Google Scholar
• Bacon B R, Tavill A S. Role of the liver in normal iron metabolism. Semin Liver Dis 1984; 4: 181–192
   PubMedGoogle Scholar
• Trinder D, Morgan E, Baker E. The mechanisms of iron uptake by fetal rat hepatocytes in culture. Hepatology 1986; 6: 852–858
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Morton A G, Tavill A S. The control of hepatic iron uptake: correlation with transferrin synthesis. Br J Haematol 1978; 39: 497–507
   Google Scholar
• Trinder D, Batey R G, Morgan E H, Baker E. Effect of cellular iron concentration on iron uptake by hepatocytes. Am J Physiol Gastrointest Liver Physiol 1990; 259: G611–G617
   Google Scholar
• Chua A CG, Herbison C E, Drake S F, Graham R M, Olynyk J K, Trinder D. Iron uptake by transferrin receptor 1 is regulated by HFE in hepatocytes. Hepatology 2006; 44: 432A
   Google Scholar
• Kobune M, Kohgo Y, Kato J, Miyazaki E, Niitsu Y. Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats. Hepatology 1994; 19: 1468–1475
   PubMed Web of Science ®Google Scholar
• Barisani D, Cairo G, Ginelli E, Marozzi A, Conte D. Nitric oxide reduces nontransferrin-bound iron transport in HepG2 cells. Hepatology 1999; 29: 464–470
   Google Scholar
• Page M A, Baker E, Morgan E H. Transferrin and iron uptake by rat hepatocytes in culture. Am J Physiol Gastrointest Liver Physiol 1984; 246: G26–G33
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Trinder D, Morgan E. Inhibition of uptake of transferrin-bound iron by human hepatoma cells by nontransferrin-bound iron. Hepatology 1997; 26: 691–698
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Thorstensen K. Hepatocytes and reticulocytes have different mechanisms for the uptake of iron from transferrin. J Biol Chem 1988; 263: 16837–16841
   PubMed Web of Science ®Google Scholar
• Scheiber B, Goldenberg H. Hepatic uptake of iron by receptor-mediated and receptor-independent mechanisms. Z Gastroenterol 1996; 34: S95–S98, (Suppl 3)
   Google Scholar
• 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
   Google Scholar
• Ose L, Ose T, Reinertsen R, Berg T. Fluid endocytosis in isolated rat parenchymal and non-parenchymal liver cells. Exp Cell Res 1980; 126: 109–119
   PubMed Web of Science ®Google Scholar
• Blomhoff R, Nenseter M S, Green M H, Berg T. A multicompartmental model of fluid-phase endocytosis in rabbit liver parenchymal cells. Biochem J 1989; 262: 605–610
   PubMed Web of Science ®Google Scholar
• Sibille J C, Octave J N, Schneider Y J, Trouet A, Crichton R R. Transferrin protein and iron uptake by cultured hepatocytes. FEBS Lett 1982; 150: 365–369
   PubMed Web of Science ®Google Scholar
• Grootveld M, Bell J D, Halliwell B, Aruoma O I, Bomford A, Sadler P J. Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy. J Biol Chem 1989; 264: 4417–4422
   PubMed Web of Science ®Google Scholar
• Gosriwatana I, Loreal O, Lu S, Brissot P, Porter J, Hider R C. Quantification of non-transferrin-bound iron in the presence of unsaturated transferrin. Anal Biochem 1999; 273: 212–220
   PubMed Web of Science ®Google Scholar
• Breuer W, Ronson A, Slotki I N, Abramov A, Hershko C, Cabantchik Z I. The assessment of serum nontransferrin-bound iron in chelation therapy and iron supplementation. Blood 2000; 95: 2975–2982
   PubMed Web of Science ®Google Scholar
• Porter J B, Abeysinghe R D, Marshall L, Hider R C, Singh S. Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. Blood 1996; 88: 705–713
   PubMed Web of Science ®Google Scholar
• McNamara L, MacPhail A P, Mandishona E, Bloom P, Paterson A C, Rouault T A, Gordeuk V R. Non-transferrin-bound iron and hepatic dysfunction in African dietary iron overload. J Gastroenterol Hepatol 1999; 14: 126–132
   Google Scholar
• Hamill R L, Woods J C, Cook B A. Congenital atransferrinemia. A case report and review of the literature. Am J Clin Pathol 1991; 96: 215–218
   PubMed Web of Science ®Google Scholar
• Simpson R J, Cooper C E, Raja K B, Halliwell B, Evans P J, Aruoma O I, Singh S, Konijn A M. Non-transferrin-bound iron species in the serum of hypotransferrinaemic mice. Biochim Biophys Acta 1992; 1156: 19–26
   PubMedGoogle Scholar
• al-Refaie F N, Wickens D G, Wonke B, Kontoghiorghes G J, Hoffbrand A V. Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol 1992; 82: 431–436
   PubMed Web of Science ®Google Scholar
• Aruoma O I, Bomford A, Polson R J, Halliwell B. Nontransferrin-bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy. Blood 1988; 72: 1416–1419
   PubMedGoogle Scholar
• Breuer W, Hershko C, Cabantchik Z I. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci 2000; 23: 185–192
   PubMedGoogle Scholar
• Brissot P, Wright T L, Ma W L, Weisiger R A. Efficient clearance of non-transferrin-bound iron by rat liver. Implications for hepatic iron loading in iron overload states. J Clin Invest 1985; 76: 1463–1470
   PubMed Web of Science ®Google Scholar
• Zimelman A P, Zimmerman H J, McLean R, Weintraub L R. Effect of iron saturation of transferrin on hepatic iron uptake: an in vitro study. Gastroenterology 1977; 72: 129–131
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Wright T L, Brissot P, Ma W L, Weisiger R A. Characterization of non-transferrin-bound iron clearance by rat liver. J Biol Chem 1986; 261: 10909–10914
   PubMedGoogle Scholar
• Wright T L, Fitz J G, Weisiger R A. Non-transferrin-bound iron uptake by rat liver. Role of membrane potential difference. J Biol Chem 1988; 263: 1842–1847
   PubMed Web of Science ®Google Scholar
• Parkes J G, Randell E W, Olivieri N F, Templeton D M. Modulation by iron loading and chelation of the uptake of non-transferrin-bound iron by human liver cells. Biochim Biophys Acta 1995; 1243: 373–380
   PubMed Web of Science ®Google Scholar
• Barisani D, Berg C L, Wessling-Resnick M, Gollan J L. Evidence for a low Km transporter for non-transferrin-bound iron in isolated rat hepatocytes. Am J Physiol Gastrointest Liver Physiol 1995; 269: G570–G576
   Google Scholar
• Graham R M, Morgan E H, Baker E. Characterisation of citrate and iron citrate uptake by cultured rat hepatocytes. J Hepatol 1998; 29: 603–613
   PubMed Web of Science ®Google Scholar
• Scheiber B, Goldenberg H. The surface of rat hepatocytes can transfer iron from stable chelates to external acceptors. Hepatology 1998; 27: 1075–1080
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Richardson D R, Chua A CG, Baker E. Activation of an iron uptake mechanism from transferrin in hepatocytes by small-molecular-weight iron complexes: implications for the pathogenesis of iron-overload disease. J Lab Clin Med 1999; 133: 144–151
   PubMed Web of Science ®Google Scholar
• 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
• Trinder D, Morgan E. Mechanisms of ferric citrate uptake by human hepatoma cells. Am J Physiol Gastrointest Liver Physiol 1998; 275: G279–G286
   Google Scholar
• Gunshin H, Fujiwara Y, Custodio A O, Direnzo C, Robine S, Andrews N C. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 2005; 115: 1258–1266
   PubMed Web of Science ®Google Scholar
• Oudit G Y, Sun H, Trivieri M G, Koch S E, Dawood F, Ackerley C, Yazdanpanah M, Wilson G J, Schwartz A, Liu P P, Backx P H. L-type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med 2003; 9: 1187–1194
   PubMed Web of Science ®Google Scholar
• Liuzzi J P, Aydemir F, Nam H, Knutson M D, Cousins R J. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci USA 2006; 103: 13612–13617
   PubMed Web of Science ®Google Scholar
• Chua A CG, Ingram H A, Raymond K N, Baker E. Multidentate pyridinones inhibit the metabolism of nontransferrin-bound iron by hepatocytes and hepatoma cells. Eur J Biochem 2003; 270: 1689–1698
   Google Scholar
• Hershko C, Link G, Pinson A. Modification of iron uptake and lipid peroxidation by hypoxia, ascorbic acid, and alpha-tocopherol in iron-loaded rat myocardial cell cultures. J Lab Clin Med 1987; 110: 355–361
   PubMed Web of Science ®Google Scholar
• Adams P C, Powell L W, Halliday J W. Isolation of a human hepatic ferritin receptor. Hepatology 1988; 8: 719–721
   PubMedGoogle Scholar
• Osterloh K, Aisen P. Pathways in the binding and uptake of ferritin by hepatocytes. Biochim Biophys Acta 1989; 1011: 40–45
   PubMed Web of Science ®Google Scholar
• Smith A, Morgan W T. Hemopexin-mediated transport of heme into isolated rat hepatocytes. J Biol Chem 1981; 256: 10902–10909
   PubMed Web of Science ®Google Scholar
• Smith A, Hunt R C. Hemopexin joins transferrin as representative members of a distinct class of receptor-mediated endocytic transport systems. Eur J Cell Biol 1990; 53: 234–245
   Google Scholar
• Ponka P, Schulman H M. Distinct features of iron metabolism in erythroid cells: implications for heme synthesis regulation. Adv Exp Med Biol 1994; 356: 173–187
   PubMedGoogle Scholar
• Anderson G J, Frazer D M. Hepatic iron metabolism. Semin Liver Dis 2005; 25: 420–432
   PubMed Web of Science ®Google Scholar
• Baker E, Page M, Morgan E H. Transferrin and iron release from rat hepatocytes in culture. Am J Physiol Gastrointest Liver Physiol 1985; 248: G93–G97
   PubMed Web of Science ®Google Scholar
• Chua A CG, Drake S F, Herbison C E, Olynyk J K, Leedman P J, Trinder D. Limited iron export by hepatocytes contributes to hepatic iron-loading in the Hfe knockout mouse. J Hepatol 2006; 44: 176–182
   Google Scholar
• Baker E, Morton A G, Tavill A S. The regulation of iron release from the perfused rat liver. Br J Haematol 1980; 45: 607–620
   PubMed Web of Science ®Google Scholar
• Baker E, Vicary F R, Huehns E R. Iron release from isolated hepatocytes. Br J Haematol 1981; 47: 493–504
   PubMed Web of Science ®Google Scholar
• Young S P, Fahmy M, Golding S. Ceruloplasmin, transferrin and apotransferrin facilitate iron release from human liver cells. FEBS Lett 1997; 411: 93–96
   PubMed Web of Science ®Google Scholar
• Casey J L, Koeller D M, Ramin V C, Klausner R D, Harford J B. Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3′ untranslated region of the mRNA. EMBO J 1989; 8: 3693–3699
   PubMed Web of Science ®Google Scholar
• Rouault T A, Stout C D, Kaptain S, Harford J B, Klausner R D. Structural relationship between an iron-regulated RNA-binding protein (IRE-BP) and aconitase: functional implications. Cell 1991; 64: 881–883
   PubMed Web of Science ®Google Scholar
• Klausner R D, Rouault T A, Harford J B. Regulating the fate of mRNA: the control of cellular iron metabolism. Cell 1993; 72: 19–28
   PubMed Web of Science ®Google Scholar
• Ponka P, Beaumont C, Richardson D R. Function and regulation of transferrin and ferritin. Semin Hematol 1998; 35: 35–54
   PubMed Web of Science ®Google Scholar
• Guo B, Phillips J D, Yu Y, Leibold E A. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem 1995; 270: 21645–21651
   PubMed Web of Science ®Google Scholar
• Hentze M W, Kuhn L C. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci USA 1996; 93: 8175–8182
   PubMed Web of Science ®Google Scholar
• Yang F, Wang X, Haile D J, Piantadosi C A, Ghio A J. Iron increases expression of iron-export protein MTP1 in lung cells. Am J Physiol Lung Cell Mol Physiol 2002; 283: L932–L939
   Google Scholar
• Kuriyama-Matsumura K, Sato H, Yamaguchi M, Bannai S. Regulation of ferritin synthesis and iron regulatory protein 1 by oxygen in mouse peritoneal macrophages. Biochem Biophys Res Commun 1998; 249: 241–246
   Google Scholar
• Hanson E S, Foot L M, Leibold E A. Hypoxia post-translationally activates iron-regulatory protein 2. J Biol Chem 1999; 274: 5047–5052
   PubMed Web of Science ®Google Scholar
• Hanson E S, Rawlins M L, Leibold E A. Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 2003; 278: 40337–40342
   PubMed Web of Science ®Google Scholar
• Pantopoulos K, Hentze M W. Nitric oxide signaling to iron-regulatory protein: direct control of ferritin mRNA translation and transferrin receptor mRNA stability in transfected fibroblasts. Proc Natl Acad Sci USA 1995; 92: 1267–1271
   PubMed Web of Science ®Google Scholar
• Pantopoulos K, Hentze M W. Rapid responses to oxidative stress mediated by iron regulatory protein. EMBO J 1995; 14: 2917–2924
   PubMed Web of Science ®Google Scholar
• Pantopoulos K, Weiss G, Hentze M W. Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 1996; 16: 3781–3788
   PubMed Web of Science ®Google Scholar
• Kim S, Ponka P. Nitrogen monoxide-mediated control of ferritin synthesis: implications for macrophage iron homeostasis. Proc Natl Acad Sci USA 2002; 99: 12214–12219
   PubMed Web of Science ®Google Scholar
• Tran T N, Eubanks S K, Schaffer K J, Zhou C Y, Linder M C. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood 1997; 90: 4979–4986
   PubMed Web of Science ®Google Scholar
• Torti F M, Torti S V. Regulation of ferritin genes and protein. Blood 2002; 99: 3505–3516
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen B K, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113: 1271–1276
   PubMed Web of Science ®Google Scholar
• 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: 1906–1910
   PubMed Web of Science ®Google Scholar
• Semenza G L. Perspectives on oxygen sensing. Cell 1999; 98: 281–284
   PubMed Web of Science ®Google Scholar
• Wang G L, Semenza G L. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995; 270: 1230–1237
   PubMed Web of Science ®Google Scholar
• Rolfs A, Kvietikova I, Gassmann M, Wenger R H. Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem 1997; 272: 20055–20062
   PubMed Web of Science ®Google Scholar
• Bianchi L, Tacchini L, Cairo G. HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res 1999; 27: 4223–4227
   PubMed Web of Science ®Google Scholar
• Lok C N, Ponka P. Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 1999; 274: 24147–24152
   PubMed Web of Science ®Google Scholar
• Mukhopadhyay C K, Mazumder B, Fox P L. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem 2000; 275: 21048–21054
   PubMed Web of Science ®Google Scholar
• Nicolas G, Chauvet C, Viatte L, Danan J L, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110: 1037–1044
   PubMed Web of Science ®Google Scholar
• Yeh K Y, Yeh M, Watkins J A, Rodriguez-Paris J, Glass J. Dietary iron induces rapid changes in rat intestinal divalent metal transporter expression. Am J Physiol Gastrointest Liver Physiol 2000; 279: G1070–G1079
   Web of Science ®Google Scholar
• Davis R J, Meisner H. Regulation of transferrin receptor cycling by protein kinase C is independent of receptor phosphorylation at serine 24 in Swiss 3T3 fibroblasts. J Biol Chem 1987; 262: 16041–16047
   PubMedGoogle Scholar
• Schonhorn J E, Akompong T, Wessling-Resnick M. Mechanism of transferrin receptor down-regulation in K562 cells in response to protein kinase C activation. J Biol Chem 1995; 270: 3698–3705
   PubMedGoogle Scholar
• Klausner R D, Harford J, van Renswoude J. Rapid internalization of the transferrin receptor in K562 cells is triggered by ligand binding or treatment with a phorbol ester. Proc Natl Acad Sci USA 1984; 81: 3005–3009
   PubMed Web of Science ®Google Scholar
• Fourie A M, Yang Y. Molecular requirements for assembly and intracellular transport of class I major histocompatibility complex molecules. Curr Top Microbiol Immunol 1998; 232: 49–74
   Google Scholar
• Cardoso C S, de Sousa M. HFE, the MHC and hemochromatosis: paradigm for an extended function for MHC class I. Tissue Antigens 2003; 61: 263–275
   Google Scholar
• Fleming R E, Sly W S. Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol 2002; 64: 663–680
   PubMed Web of Science ®Google Scholar
• Bjorkman P J, Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 1990; 59: 253–288
   PubMed Web of Science ®Google Scholar
• Parkkila S, Waheed A, Britton R S, Feder J N, Tsuchihashi Z, Schatzman R C, Bacon B R, Sly W S. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA 1997; 94: 2534–2539
   PubMed Web of Science ®Google Scholar
• Waheed A, Parkkila S, Saarnio J, Fleming R E, Zhou X Y, Tomatsu S, Britton R S, Bacon B R, Sly W S. Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci USA 1999; 96: 1579–1584
   PubMed Web of Science ®Google Scholar
• Holmstrom P, Dzikaite V, Hultcrantz R, Melefors O, Eckes K, Stal P, Kinnman N, Smedsrod B, Gafvels M, Eggertsen G. Structure and liver cell expression pattern of the HFE gene in the rat. J Hepatol 2003; 39: 308–314
   Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• 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
   Google Scholar
• Parkkila S, Parkkila A K, Waheed A, Britton R S, Zhou X Y, Fleming R E, Tomatsu S, Bacon B R, Sly W S. Cell surface expression of HFE protein in epithelial cells, macrophages, and monocytes. Haematologica 2000; 85: 340–345
   PubMed Web of Science ®Google Scholar
• Feder J N, Tsuchihashi Z, Irrinki A, Lee V K, Mapa F A, Morikang E, Prass C E, Starnes S M, Wolff R K, Parkkila S, Sly W S, Schatzman R C. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem 1997; 272: 14025–14028
   PubMed Web of Science ®Google Scholar
• Waheed A, Parkkila S, Zhou X Y, Tomatsu S, Tsuchihashi Z, Feder J N, Schatzman R C, Britton R S, Bacon B R, Sly W S. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997; 94: 12384–12389
   PubMed Web of Science ®Google Scholar
• Gross C N, Irrinki A, Feder J N, Enns C A. Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation. J Biol Chem 1998; 273: 22068–22074
   PubMed Web of Science ®Google Scholar
• Santos M, Schilham M W, Rademakers L H, Marx J J, de Sousa M, Clevers H. Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med 1996; 184: 1975–1985
   PubMed Web of Science ®Google Scholar
• Ramalingam T S, West A P, Jr., Lebron J A, Nangiana J S, Hogan T H, Enns C A, Bjorkman P J. Binding to the transferrin receptor is required for endocytosis of HFE and regulation of iron homeostasis. Nat Cell Biol 2000; 2: 953–957
   PubMed Web of Science ®Google Scholar
• Giannetti A M, Bjorkman P J. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem 2004; 279: 25866–25875
   PubMedGoogle Scholar
• Lebron J A, Bennett M J, Vaughn D E, Chirino A J, Snow P M, Mintier G A, Feder J N, Bjorkman P J. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 1998; 93: 111–123
   PubMed Web of Science ®Google Scholar
• Davies P S, Zhang A S, Anderson E L, Roy C N, Lampson M A, McGraw T E, Enns C A. Evidence for the interaction of the hereditary haemochromatosis protein, HFE, with the transferrin receptor in endocytic compartments. Biochem J 2003; 373: 145–153
   PubMed Web of Science ®Google Scholar
• Riedel H D, Muckenthaler M U, Gehrke S G, Mohr I, Brennan K, Herrmann T, Fitscher B A, Hentze M W, Stremmel W. HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 1999; 94: 3915–3921
   PubMedGoogle Scholar
• Roy C N, Penny D M, Feder J N, Enns C A. The hereditary hemochromatosis protein, HFE, specifically regulates transferrin-mediated iron uptake in HeLa cells. J Biol Chem 1999; 274: 9022–9028
   PubMedGoogle Scholar
• Corsi B, Levi S, Cozzi A, Corti A, Altimare D, Albertini A, Arosio P. Overexpression of the hereditary hemochromatosis protein, HFE, in HeLa cells induces and iron-deficient phenotype. FEBS Lett 1999; 460: 149–152
   PubMedGoogle Scholar
• Salter-Cid L, Brunmark A, Li Y, Leturcq D, Peterson P A, Jackson M R, Yang Y. Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Proc Natl Acad Sci USA 1999; 96: 5434–5439
   PubMed Web of Science ®Google Scholar
• Ikuta K, Fujimoto Y, Suzuki Y, Tanaka K, Saito H, Ohhira M, Sasaki K, Kohgo Y. Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells. Biochim Biophys Acta 2000; 1496: 221–231
   Google Scholar
• Waheed A, Grubb J H, Zhou X Y, Tomatsu S, Fleming R E, Costaldi M E, Britton R S, Bacon B R, Sly W S. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci USA 2002; 99: 3117–3122
   PubMed Web of Science ®Google Scholar
• Wang J, Chen G, Pantopoulos K. The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin. Biochem J 2003; 370: 891–899
   Google Scholar
• Montosi G, Paglia P, Garuti C, Guzman C A, Bastin J M, Colombo M P, Pietrangelo A. Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. Blood 2000; 96: 1125–1129
   PubMed Web of Science ®Google Scholar
• Drakesmith H, Sweetland E, Schimanski L, Edwards J, Cowley D, Ashraf M, Bastin J, Townsend A R. The hemochromatosis protein HFE inhibits iron export from macrophages. Proc Natl Acad Sci USA 2002; 99: 15602–15607
   PubMed Web of Science ®Google Scholar
• Davies P S, Enns C A. Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells. J Biol Chem 2004; 279: 25085–25092
   Google Scholar
• Camaschella C, Roetto A, Cali A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000; 25: 14–15
   PubMed Web of Science ®Google Scholar
• Roetto A, Totaro A, Piperno A, Piga A, Longo F, Garozzo G, Cali A, De Gobbi M, Gasparini P, Camaschella C. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 2001; 97: 2555–2560
   PubMed Web of Science ®Google Scholar
• Fleming R E, Ahmann J R, Migas M C, Waheed A, Koeffler H P, Kawabata H, Britton R S, Bacon B R, Sly W S. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci USA 2002; 99: 10653–10658
   PubMedGoogle Scholar
• Calzolari A, Raggi C, Deaglio S, Sposi N M, Stafsnes M, Fecchi K, Parolini I, Malavasi F, Peschle C, Sargiacomo M, Testa U. TfR2 localizes in lipid raft domains and is released in exosomes to activate signal transduction along the MAPK pathway. J Cell Sci 2006; 119: 4486–4498
   PubMed Web of Science ®Google Scholar
• Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, Loreal O. 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
   PubMed Web of Science ®Google Scholar
• Kulaksiz H, Theilig F, Bachmann S, Gehrke S G, Rost D, Janetzko A, Cetin Y, Stremmel W. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 2005; 184: 361–370
   PubMed Web of Science ®Google Scholar
• Hunter H N, Fulton D B, Ganz T, Vogel H J. 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: 37597–37603
   PubMed Web of Science ®Google Scholar
• Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S. Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis 2002; 29: 327–335
   PubMed Web of Science ®Google Scholar
• Nemeth E, Preza G C, Jung C L, Kaplan J, Waring A J, Ganz T. The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood 2006; 107: 328–333
   PubMed Web of Science ®Google Scholar
• Frazer D M, Wilkins S J, Becker E M, Vulpe C D, McKie A T, Trinder D, Anderson G J. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 2002; 123: 835–844
   PubMed Web of Science ®Google Scholar
• Ahmad K A, Ahmann J R, Migas M C, Waheed A, Britton R S, Bacon B R, Sly W S, Fleming R E. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis 2002; 29: 361–366
   PubMed Web of Science ®Google Scholar
• Bridle K R, Frazer D M, Wilkins S J, Dixon J L, Purdie D M, Crawford D H, Subramaniam V N, Powell L W, Anderson G J, Ramm G A. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003; 361: 669–673
   PubMed Web of Science ®Google Scholar
• Muckenthaler M, Roy C N, Custodio A O, Minana B, de Graaf J, Montross L K, Andrews N C, Hentze M W. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 2003; 34: 102–107
   PubMed Web of Science ®Google Scholar
• Kawabata H, Fleming R E, Gui D, Moon S Y, Saitoh T, O'Kelly J, Umehara Y, Wano Y, Said J W, Koeffler H P. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 2005; 105: 376–381
   PubMed Web of Science ®Google Scholar
• Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood 2005; 105: 1803–1806
   PubMed Web of Science ®Google Scholar
• Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, Vaulont S. 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
   PubMed Web of Science ®Google Scholar
• Papanikolaou G, Tzilianos M, Christakis J I, Bogdanos D, Tsimirika K, MacFarlane J, Goldberg Y P, Sakellaropoulos N, Ganz T, Nemeth E. Hepcidin in iron overload disorders. Blood 2005; 105: 4103–4105
   PubMed Web of Science ®Google Scholar
• Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 2005; 115: 2180–2186
   PubMed Web of Science ®Google Scholar
• Huang F W, Pinkus J L, Pinkus G S, Fleming M D, Andrews N C. A mouse model of juvenile hemochromatosis. J Clin Invest 2005; 115: 2187–2191
   PubMed Web of Science ®Google Scholar
• Laftah A H, Ramesh B, Simpson R J, Solanky N, Bahram S, Schumann K, Debnam E S, Srai S K. Effect of hepcidin on intestinal iron absorption in mice. Blood 2004; 103: 3940–3944
   PubMed Web of Science ®Google Scholar
• Nicolas G, Viatte L, Lou D Q, Bennoun M, Beaumont C, Kahn A, Andrews N C, Vaulont S. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 2003; 34: 97–101
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Delaby C, Pilard N, Goncalves A S, 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: 3979–3984
   PubMed Web of Science ®Google Scholar
• Nemeth E, Valore E V, 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: 2461–2463
   PubMed Web of Science ®Google Scholar
• Roy C N, Custodio A O, de Graaf J, Schneider S, Akpan I, Montross L K, Sanchez M, Gaudino A, Hentze M W, Andrews N C, Muckenthaler M U. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Nat Genet 2004; 36: 481–485
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Leung P S, Srai S K, Mascarenhas M, Churchill L J, Debnam E S. Increased duodenal iron uptake and transfer in a rat model of chronic hypoxia is accompanied by reduced hepcidin expression. Gut 2005; 54: 1391–1395
   PubMed Web of Science ®Google Scholar
• Courselaud B, Pigeon C, Inoue Y, Inoue J, Gonzalez F J, Leroyer P, Gilot D, Boudjema K, Guguen-Guillouzo C, Brissot P, Loreal O, Ilyin G. C/EBPalpha regulates hepatic transcription of he 1pcidin, an antimicrobial peptide and regulator of iron metabolism. Cross-talk between C/EBP pathway and iron metabolism. J Biol Chem 2002; 277: 41163–41170
   PubMed Web of Science ®Google Scholar
• Wrighting D M, Andrews N C. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006; 108: 3204–3209
   PubMed Web of Science ®Google Scholar
• Wang R H, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng C X. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005; 2: 399–409
   PubMed Web of Science ®Google Scholar
• Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003; 113: 685–700
   PubMed Web of Science ®Google Scholar
• Chen D, Zhao M, Mundy G R. Bone morphogenetic proteins. Growth Factors 2004; 22: 233–241
   PubMed Web of Science ®Google Scholar
• Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci USA 2006; 103: 10289–10293
   PubMed Web of Science ®Google Scholar
• Babitt J L, Huang F W, Wrighting D M, Xia Y, Sidis Y, Samad T A, Campagna J A, Chung R T, Schneyer A L, Woolf C J, Andrews N C, Lin H Y. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006; 38: 531–539
   PubMed Web of Science ®Google Scholar
• Monnier P P, Sierra A, Macchi P, Deitinghoff L, Andersen J S, Mann M, Flad M, Hornberger M R, Stahl B, Bonhoeffer F, Mueller B K. RGM is a repulsive guidance molecule for retinal axons. Nature 2002; 419: 392–395
   PubMedGoogle Scholar
• Lin L, Goldberg Y P, Ganz T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood 2005; 106: 2884–2889
   PubMed Web of Science ®Google Scholar
• Zhang A S, West A P, Jr., Wyman A E, Bjorkman P J, Enns C A. Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells. J Biol Chem 2005; 280: 33885–33894
   Google Scholar
• Krijt J, Vokurka M, Chang K T, Necas E. Expression of Rgmc, the murine ortholog of hemojuvelin gene, is modulated by development and inflammation, but not by iron status or erythropoietin. Blood 2004; 104: 4308–4310
   Google Scholar
• Keeling S L, Gad J M, Cooper H M. Mouse Neogenin, a DCC-like molecule, has four splice variants and is expressed widely in the adult mouse and during embryogenesis. Oncogene 1997; 15: 691–700
   Google Scholar
• Finch C. Regulators of iron balance in humans. Blood 1994; 84: 1697–1702
   PubMed Web of Science ®Google Scholar
• Sayers M H, English G, Finch C. Capacity of the store-regulator in maintaining iron balance. Am J Hematol 1994; 47: 194–197
   PubMed Web of Science ®Google Scholar
• Bothwell T H, Pirzio-Biroli G, Finch C A. Iron absorption. I. Factors influencing absorption. J Lab Clin Med 1958; 51: 24–36
   PubMed Web of Science ®Google Scholar
• Andrews N C. Iron metabolism: iron deficiency and iron overload. Annu Rev Genomics Hum Genet 2000; 1: 75–98
   PubMed Web of Science ®Google Scholar
• Cazzola M, Beguin Y, Bergamaschi G, Guarnone R, Cerani P, Barella S, Cao A, Galanello R. Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis. Br J Haematol 1999; 106: 752–755
   Google Scholar
• Cook J D, Skikne B S, Baynes R D. Serum transferrin receptor. Annu Rev Med 1993; 44: 63–74
   PubMed Web of Science ®Google Scholar
• Khumalo H, Gomo Z A, Moyo V M, Gordeuk V R, Saungweme T, Rouault T A, Gangaidzo I T. Serum transferrin receptors are decreased in the presence of iron overload. Clin Chem 1998; 44: 40–44
   PubMed Web of Science ®Google Scholar
• Hahn P F, Bale W F, Ross J F, Balfour W M, Whipple G H. Radioactive iron absorption by the gastrointestinal tract: influence of anemia, anoxia and antecedent feeding. J Exp Med 1943; 78: 169–188
   PubMedGoogle Scholar
• Oates P S, Thomas C, Freitas E, Callow M J, Morgan E H. Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats. Am J Physiol Gastrointest Liver Physiol 2000; 278: G930–G936
   Google Scholar
• Bothwell T H. The control of iron absorption. Br J Haematol 1968; 14: 453–456
   PubMed Web of Science ®Google Scholar
• Cook J D, Barry W E, Hershko C, Fillet G, Finch C A. Iron kinetics with emphasis on iron overload. Am J Pathol 1973; 72: 337–343
   PubMed Web of Science ®Google Scholar
• Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 2004; 350: 2383–2397
   PubMed Web of Science ®Google Scholar
• Conrad M E, Weintraub L R, Crosby W H. The role of the intestine in iron kinetics. J Clin Invest 1964; 43: 963–974
   PubMed Web of Science ®Google Scholar
• Bedard Y C, Pinkerton P H, Simon G T. Uptake of circulating iron by the duodenum of normal mice and mice with altered iron stores, including sex-linked anemia: high resolution radioautographic study. Lab Invest 1976; 34: 611–615
   PubMed Web of Science ®Google Scholar
• Thomson A B, Valberg L S. Kinetics of intestinal iron absorption in the rat: effect of cobalt. Am J Physiol 1971; 220: 1080–1085
   Google Scholar
• Acheson L S, Schultz S G. Iron influx across the brush border of rabbit duodenum: effects of anemia and iron loading. Biochim Biophys Acta 1972; 255: 479–483
   Google Scholar
• Pietrangelo A, Rocchi E, Casalgrandi G, Rigo G, Ferrari A, Perini M, Ventura E, Cairo G. Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum. Gastroenterology 1992; 102: 802–809
   PubMed Web of Science ®Google Scholar
• Pietrangelo A, Casalgrandi G, Quaglino D, Gualdi R, Conte D, Milani S, Montosi G, Cesarini L, Ventura E, Cairo G. Duodenal ferritin synthesis in genetic hemochromatosis. Gastroenterology 1995; 108: 208–217
   PubMed Web of Science ®Google Scholar
• Zoller H, Koch R O, Theurl I, Obrist P, Pietrangelo A, Montosi G, Haile D J, Vogel W, Weiss G. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload. Gastroenterology 2001; 120: 1412–1419
   PubMed Web of Science ®Google Scholar
• Ajioka R S, Levy J E, Andrews N C, Kushner J P. Regulation of iron absorption in Hfe mutant mice. Blood 2002; 100: 1465–1469
   Google Scholar