Comprehensive Physiology Wiley Online Library

Iron Homeostasis in the Liver

Full Article on Wiley Online Library



Abstract

Iron is an essential nutrient that is tightly regulated. A principal function of the liver is the regulation of iron homeostasis. The liver senses changes in systemic iron requirements and can regulate iron concentrations in a robust and rapid manner. The last 10 years have led to the discovery of several regulatory mechanisms in the liver that control the production of iron regulatory genes, storage capacity, and iron mobilization. Dysregulation of these functions leads to an imbalance of iron, which is the primary cause of iron‐related disorders. Anemia and iron overload are two of the most prevalent disorders worldwide and affect over a billion people. Several mutations in liver‐derived genes have been identified, demonstrating the central role of the liver in iron homeostasis. During conditions of excess iron, the liver increases iron storage and protects other tissues, namely, the heart and pancreas from iron‐induced cellular damage. However, a chronic increase in liver iron stores results in excess reactive oxygen species production and liver injury. Excess liver iron is one of the major mechanisms leading to increased steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. © 2013 American Physiological Society. Compr Physiol 3:315‐330, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Systemic iron regulation. Dietary iron is absorbed through the small intestine and mainly utilized for red blood cell (RBC) production. Hepatic and splenic macrophages recycle iron from senescent RBCs. The iron derived from recycling is used for production of RBCs. During times of iron excess the liver can store iron and during increased systemic needs the liver can mobilize iron stores for utilization.

Figure 2. Figure 2.

Hepcidin regulation of ferroportin (FPN) protein expression during changes in systemic iron levels. High iron levels increase hepcidin expression, which decrease iron export from the small intestine and macrophage due to an internalization and degradation of FPN. Iron deficiency results in a decrease in hepcidin levels and stabilization of FPN protein expression.

Figure 3. Figure 3.

Regulation of hepcidin by bone morphogenetic protein (BMP)/SMAD, inflammatory and hypoxia/erythropoietic signaling in the liver. Three major pathways are critical for regulating basal and stimuli‐induced hepcidin expression. Binding of iron containing transferrin (Tf) to transferrin receptor 1 (Tfr1) causes a dissociation of Tfr1‐High Fe (HFE) complex and an interaction of HFE with Tfr2. Increased stabilization of Tfr2 increases BMP6‐mediated phosphorylation of SMAD1/5/8 and recruitment of SMAD 1/5/8 and SMAD4 to the hepcidin proximal promoter. BMP/SMAD signaling is the major pathway by which hepcidin expression is coordinated to meet systemic iron requirements. Activation of hepcidin by inflammation is thought to act independently of the BMP/SMAD pathway. The best‐studied mechanism is via the proinflammatory mediator IL‐6. Binding of IL‐6 to its receptor IL‐6 receptor (IL‐6R) initiates activation of the JAK‐STAT3 pathway. STAT3 binds directly to the proximal promoter to increase hepcidin expression. Hypoxia and erythropoiesis are inhibitors of hepcidin expression and these are the least understood pathways by which hepcidin expression is regulated. Hypoxia and erythropoiesis have been shown to inhibit hepcidin expression via direct binding of hypoxia‐inducible factor (HIF) to the proximal promoter, an erythropoietin (EPO)‐EPO receptor (EPOR)‐mediated decrease in C/EBPα expression, and through increase in an unknown erythroid derived factor which signals through an undefined pathway.

Figure 4. Figure 4.

Mechanisms of liver iron uptake. Iron is imported into the liver via Tf/Tfr‐mediated endocytosis. As the pH of the endocytic vesicle drops, iron is released, reduced to Fe2+ by an endocytic reductase, and transported out by DMT1 and/or ZIP14. During iron overload a significant amount of NTBI is present. Iron can be directly transported into the liver through membrane bound DMT1 and/or ZIP14. During conditions of increased hemolysis, the liver is capable of transport of hemoglobin and heme. Free hemoglobin binds with high affinity to haptoglobin, whereas free heme binds to hemopexin. These complexes bind to their respective receptors CD163 and Lrp/CD91, which initiate receptor‐meditated endocytosis. Hemoglobin is degraded in the endosome and heme is released from the endocytic vesicle. Heme is further degraded by HO‐1 releasing iron.

Figure 5. Figure 5.

Iron‐induced liver damage. Iron accumulation in hepatocytes and Kupffer cells leads to an increase in reactive oxygen species (ROS) production and proinflammatory mediators. Both ROS and proinflammatory mediators initiate a feed forward cycle, which activates stellate cells, initiates cell damage, and leads to loss of function contributing to an increase in steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).



Figure 1.

Systemic iron regulation. Dietary iron is absorbed through the small intestine and mainly utilized for red blood cell (RBC) production. Hepatic and splenic macrophages recycle iron from senescent RBCs. The iron derived from recycling is used for production of RBCs. During times of iron excess the liver can store iron and during increased systemic needs the liver can mobilize iron stores for utilization.



Figure 2.

Hepcidin regulation of ferroportin (FPN) protein expression during changes in systemic iron levels. High iron levels increase hepcidin expression, which decrease iron export from the small intestine and macrophage due to an internalization and degradation of FPN. Iron deficiency results in a decrease in hepcidin levels and stabilization of FPN protein expression.



Figure 3.

Regulation of hepcidin by bone morphogenetic protein (BMP)/SMAD, inflammatory and hypoxia/erythropoietic signaling in the liver. Three major pathways are critical for regulating basal and stimuli‐induced hepcidin expression. Binding of iron containing transferrin (Tf) to transferrin receptor 1 (Tfr1) causes a dissociation of Tfr1‐High Fe (HFE) complex and an interaction of HFE with Tfr2. Increased stabilization of Tfr2 increases BMP6‐mediated phosphorylation of SMAD1/5/8 and recruitment of SMAD 1/5/8 and SMAD4 to the hepcidin proximal promoter. BMP/SMAD signaling is the major pathway by which hepcidin expression is coordinated to meet systemic iron requirements. Activation of hepcidin by inflammation is thought to act independently of the BMP/SMAD pathway. The best‐studied mechanism is via the proinflammatory mediator IL‐6. Binding of IL‐6 to its receptor IL‐6 receptor (IL‐6R) initiates activation of the JAK‐STAT3 pathway. STAT3 binds directly to the proximal promoter to increase hepcidin expression. Hypoxia and erythropoiesis are inhibitors of hepcidin expression and these are the least understood pathways by which hepcidin expression is regulated. Hypoxia and erythropoiesis have been shown to inhibit hepcidin expression via direct binding of hypoxia‐inducible factor (HIF) to the proximal promoter, an erythropoietin (EPO)‐EPO receptor (EPOR)‐mediated decrease in C/EBPα expression, and through increase in an unknown erythroid derived factor which signals through an undefined pathway.



Figure 4.

Mechanisms of liver iron uptake. Iron is imported into the liver via Tf/Tfr‐mediated endocytosis. As the pH of the endocytic vesicle drops, iron is released, reduced to Fe2+ by an endocytic reductase, and transported out by DMT1 and/or ZIP14. During iron overload a significant amount of NTBI is present. Iron can be directly transported into the liver through membrane bound DMT1 and/or ZIP14. During conditions of increased hemolysis, the liver is capable of transport of hemoglobin and heme. Free hemoglobin binds with high affinity to haptoglobin, whereas free heme binds to hemopexin. These complexes bind to their respective receptors CD163 and Lrp/CD91, which initiate receptor‐meditated endocytosis. Hemoglobin is degraded in the endosome and heme is released from the endocytic vesicle. Heme is further degraded by HO‐1 releasing iron.



Figure 5.

Iron‐induced liver damage. Iron accumulation in hepatocytes and Kupffer cells leads to an increase in reactive oxygen species (ROS) production and proinflammatory mediators. Both ROS and proinflammatory mediators initiate a feed forward cycle, which activates stellate cells, initiates cell damage, and leads to loss of function contributing to an increase in steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).

References
 1. Abboud S, Haile DJ. A novel mammalian iron‐regulated protein involved in intracellular iron metabolism. J Biol Chem 275(26): 19906‐19912, 2000.
 2. Aigner E, Theurl I, Theurl M, Lederer D, Haufe H, Dietze O, Strasser M, Datz C, Weiss G. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 87(5): 1374‐1383, 2008.
 3. Aisen P, Brown EB. Structure and function of transferrin. Prog Hematol 9: 25‐56, 1975.
 4. Aisen P, Leibman A, Zweier J. Stoichiometric and site characteristics of the binding of iron to human transferrin. J Biol Chem 253(6): 1930‐1937, 1978.
 5. Anderson ER, Xue X, Shah YM. Intestinal hypoxia‐inducible factor‐2alpha (HIF‐2alpha) is critical for efficient erythropoiesis. J Biol Chem 286(22): 19533‐19540, 2011.
 6. Anderson GJ, Frazer DM. Iron metabolism meets signal transduction. Nat Genet 38(5): 503‐504, 2006.
 7. Andrews NC. Forging a field: The golden age of iron biology. Blood 112(2): 219‐230, 2008.
 8. Andriopoulos B, Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41(4): 482‐487, 2009.
 9. Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman R, Maxwell PH, Choi P. Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin. Haematologica 95(3): 505‐508, 2010.
 10. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, Campagna JA, Chung RT, Schneyer AL, Woolf CJ Andrews NC, Lin HY. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 38(5): 531‐539, 2006.
 11. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 117(7): 1933‐1939, 2007.
 12. Basclain KA, Shilkin KB, Withers G, Reed WD, Jeffrey GP. Cellular expression and regulation of iron transport and storage proteins in genetic haemochromatosis. J Gastroenterol Hepatol 13(6): 624‐634, 1998.
 13. Beguin Y, Huebers HA, Weber G, Eng M, Finch CA. Hepatocyte iron release in rats. J Lab Clin Med 113(3): 346‐354, 1989.
 14. Benkovic SA, Connor JR. Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. J Comp Neurol 338(1): 97‐113, 1993.
 15. Bleil JD, Bretscher MS. Transferrin receptor and its recycling in HeLa cells. Embo J 1(3): 351‐355, 1982.
 16. Bondi A, Valentino P, Daraio F, Porporato P, Gramaglia E, Carturan S, Gottardi E, Camaschella C, Roetto A. Hepatic expression of hemochromatosis genes in two mouse strains after phlebotomy and iron overload. Haematologica 90(9): 1161‐1167, 2005.
 17. Borgna‐Pignatti C, Vergine G, Lombardo T, Cappellini MD, Cianciulli P, Maggio A, Renda D, Lai ME, Mandas A, Forni G. Hepatocellular carcinoma in the thalassaemia syndromes. Br J Haematol 124(1): 114‐117, 2004.
 18. Bozzini C, Girelli D, Olivieri O, Martinelli N, Bassi A, De Matteis G, Tenuti I, Lotto V, Friso S, Pizzolo F Corrocher R. Prevalence of body iron excess in the metabolic syndrome. Diabetes care 28(8): 2061‐2063, 2005.
 19. Bradbear RA, Bain C, Siskind V, Schofield FD, Webb S, Axelsen EM, Halliday JW, Bassett ML, Powell LW. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst 75(1): 81‐84, 1985.
 20. Braliou GG, Verga Falzacappa MV, Chachami G, Casanovas G, Muckenthaler MU, Simos G. 2‐Oxoglutarate‐dependent oxygenases control hepcidin gene expression. J Hepatol 48(5): 801‐810, 2008.
 21. Brissot P, Wright TL, Ma WL, Weisiger RA. Efficient clearance of non‐transferrin‐bound iron by rat liver. Implications for hepatic iron loading in iron overload states. J Clin Invest 76(4): 1463‐1470, 1985.
 22. Bubici C, Papa S, Dean K, Franzoso G. Mutual cross‐talk between reactive oxygen species and nuclear factor‐kappa B: Molecular basis and biological significance. Oncogene 25(51): 6731‐6748, 2006.
 23. Cairo G, Tacchini L, Pogliaghi G, Anzon E, Tomasi A, Bernelli‐Zazzera A. Induction of ferritin synthesis by oxidative stress. Transcriptional and post‐transcriptional regulation by expansion of the “free” iron pool. J Biol Chem 270(2): 700‐703, 1995.
 24. 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 25(1): 14‐15, 2000.
 25. 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 93(12): 4406‐4417, 1999.
 26. Cartwright GE. The anemia of chronic disorders. Semin Hematol 3(4): 351‐375, 1966.
 27. Cartwright GE, Lauritsen MA, Jones PJ, Merrill IM, Wintrobe MM. The anemia of infection; hypoferremia, hypercupremia, and alterations in porphyrin metabolism in patients. J Clin Invest 2565‐80, 1946.
 28. Cavill I. Erythropoiesis and iron. Best Pract Res Clin Haematol 15(2): 399‐409, 2002.
 29. Chaston TB, Matak P, Pourvali K, Srai SK, McKie AT, Sharp PA. Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling. Am J Physiol Cell Physiol 300(4): C888‐C895, 2011.
 30. Cherukuri S, Potla R, Sarkar J, Nurko S, Harris ZL, Fox PL. Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab 2(5): 309‐319, 2005.
 31. Choi SO, Cho YS, Kim HL, Park JW. ROS mediate the hypoxic repression of the hepcidin gene by inhibiting C/EBPalpha and STAT‐3. Biochem Biophys Res Commun 356(1): 312‐317, 2007.
 32. Ciechanover A, Schwartz AL, Dautry‐Varsat A, Lodish HF. Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. Effect of lysosomotropic agents. J Biol Chem 258(16): 9681‐9689, 1983.
 33. Ciechanover A, Schwartz AL, Lodish HF. Sorting and recycling of cell surface receptors and endocytosed ligands: The asialoglycoprotein and transferrin receptors. J Cell Biochem 23(1‐4): 107‐130, 1983.
 34. Corradini E, Schmidt PJ, Meynard D, Garuti C, Montosi G, Chen S, Vukicevic S, Pietrangelo A, Lin HY, Babitt JL. BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 139(5): 1721‐1729, 2010.
 35. Courselaud B, Pigeon C, Inoue Y, Inoue J, Gonzalez FJ, Leroyer P, Gilot D, Boudjema K, Guguen‐Guillouzo C, Brissot P Loréal O, Ilyin G. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. Cross‐talk between C/EBP pathway and iron metabolism. J Biol Chem 277(43): 41163‐41170, 2002.
 36. Dautry‐Varsat A, Ciechanover A, Lodish HF. pH and the recycling of transferrin during receptor‐mediated endocytosis. Proc Natl Acad Sci U S A 80(8): 2258‐2262, 1983.
 37. De Domenico I, Lo E, Ward DM, Kaplan J. Hepcidin‐induced internalization of ferroportin requires binding and cooperative interaction with Jak2. Proc Natl Acad Sci U S A 106(10): 3800‐3805, 2009.
 38. De Domenico I, Vaughn MB, Li L, Bagley D, Musci G, Ward DM, Kaplan J. Ferroportin‐mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. Embo J 25(22): 5396‐5404, 2006.
 39. De Domenico I, Ward DM, Langelier C, Vaughn MB, Nemeth E, Sundquist WI, Ganz T, Musci G, Kaplan J. The molecular mechanism of hepcidin‐mediated ferroportin down‐regulation. Mol Biol Cell 18(7): 2569‐2578, 2007.
 40. De Domenico I, Ward DM, Musci G, Kaplan J. Evidence for the multimeric structure of ferroportin. Blood 109(5): 2205‐2209, 2007.
 41. De Domenico I, Ward DM, Nemeth E, Vaughn MB, Musci G, Ganz T, Kaplan J. The molecular basis of ferroportin‐linked hemochromatosis. Proc Natl Acad Sci U S A 102(25): 8955‐8960, 2005.
 42. Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target. J Hepatol 55(4): 920‐932, 2011.
 43. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1(3): 191‐200, 2005.
 44. Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, Khovananth K, Mudd S, Mann N, Moresco EM Beutler E, Beutler B. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320(5879): 1088‐1092, 2008.
 45. Fargion S, Dongiovanni P, Guzzo A, Colombo S, Valenti L, Fracanzani AL. Iron and insulin resistance. Aliment Pharmacol Ther 22(Suppl) 261‐63, 2005.
 46. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R, Jr, Ellis MC, Fullan A Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK. A novel MHC class I‐like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13(4): 399‐408, 1996.
 47. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K Andrews NC, Fleming MD. Mutations in TMPRSS6 cause iron‐refractory iron deficiency anemia (IRIDA). Nat Genet 40(5): 569‐571, 2008.
 48. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down‐regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 115(18): 3817‐3826, 2010.
 49. Fleming MD, Trenor CC, III, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 16(4): 383‐386, 1997.
 50. Fleming RE, Ahmann JR, Migas MC, Waheed A, Koeffler HP, Kawabata H, Britton RS, Bacon BR, Sly WS. Targeted mutagenesis of the murine transferrin receptor‐2 gene produces hemochromatosis. Proc Natl Acad Sci U S A 99(16): 10653‐10658, 2002.
 51. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432(7019): 917‐921, 2004.
 52. Folgueras AR, de Lara FM, Pendas AM, Garabaya C, Rodriguez F, Astudillo A, Bernal T, Cabanillas R, Lopez‐Otin C, Velasco G. Membrane‐bound serine protease matriptase‐2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112(6): 2539‐2545, 2008.
 53. Frazer DM, Inglis HR, Wilkins SJ, Millard KN, Steele TM, McLaren GD, McKie AT, Vulpe CD, Anderson GJ. Delayed hepcidin response explains the lag period in iron absorption following a stimulus to increase erythropoiesis. Gut 53(10): 1509‐1515, 2004.
 54. Frazer DM, Wilkins SJ, Becker EM, Vulpe CD, McKie AT, Trinder D, Anderson GJ. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 123(3): 835‐844, 2002.
 55. Fujita N, Takei Y. Iron overload in nonalcoholic steatohepatitis. Adv Clin Chem 55105‐132, 2011.
 56. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 117(17): 4425‐4433, 2011.
 57. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102(3): 783‐788, 2003.
 58. Ganz T. Macrophages and systemic iron homeostasis. J Innate Immun 2012 [Epub ahead of print].
 59. Ganz T, Nemeth E. The hepcidin‐ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematology Am Soc Hematol Educ Program 2011: 538‐542, 2011.
 60. Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin‐induced hepcidin expression. Cell Metab 9(3): 217‐227, 2009.
 61. Gardenghi S, Marongiu MF, Ramos P, Guy E, Breda L, Chadburn A, Liu Y, Amariglio N, Rechavi G, Rachmilewitz EA Breuer W, Cabantchik ZI, Wrighting DM, Andrews NC, de Sousa M, Giardina PJ, Grady RW, Rivella S. Ineffective erythropoiesis in beta‐thalassemia is characterized by increased iron absorption mediated by down‐regulation of hepcidin and up‐regulation of ferroportin. Blood 109(11): 5027‐5035, 2007.
 62. Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, Muirhead K, Rao N, Roy CN, Andrews NC Nemeth E, Follenzi A, An X, Mohandas N, Ginzburg Y, Rachmilewitz EA, Giardina PJ, Grady RW, Rivella S. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta‐thalassemic mice. J Clin Invest 120(12): 4466‐4477, 2010.
 63. Gattermann N. The treatment of secondary hemochromatosis. Dtsch Arztebl Int 106(30): 499‐504, 2009.
 64. Goldwurm S, Casati C, Venturi N, Strada S, Santambrogio P, Indraccolo S, Arosio P, Cazzola M, Piperno A, Masera G Biondi A. Biochemical and genetic defects underlying human congenital hypotransferrinemia. Hematol J 1(6): 390‐398, 2000.
 65. Gordeuk VR, Miasnikova GY, Sergueeva AI, Niu X, Nouraie M, Okhotin DJ, Polyakova LA, Ammosova T, Nekhai S, Ganz T Prchal JT. Chuvash polycythemia VHLR200W mutation is associated with down‐regulation of hepcidin expression. Blood 118(19): 5278‐5282, 2011.
 66. Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ. 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 264(8): 4417‐4422, 1989.
 67. Gruenheid S, Canonne‐Hergaux F, Gauthier S, Hackam DJ, Grinstein S, Gros P. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. J Exp Med 189(5): 831‐841, 1999.
 68. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest 115(5): 1258‐1266, 2005.
 69. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA. Cloning and characterization of a mammalian proton‐coupled metal‐ion transporter. Nature 388(6641): 482‐488, 1997.
 70. Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age‐related macular degeneration. Proc Natl Acad Sci U S A 101(38): 13850‐13855, 2004.
 71. Hann HW, Stahlhut MW, Blumberg BS. Iron nutrition and tumor growth: Decreased tumor growth in iron‐deficient mice. Cancer Res 48(15): 4168‐4170, 1988.
 72. Harding C, Stahl P. Transferrin recycling in reticulocytes: pH and iron are important determinants of ligand binding and processing. Biochem Biophys Res Commun 113(2): 650‐658, 1983.
 73. Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD. Aceruloplasminemia: Molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A 92(7): 2539‐2543, 1995.
 74. Hattori A, Tomosugi N, Tatsumi Y, Suzuki A, Hayashi K, Katano Y, Inagaki Y, Ishikawa T, Hayashi H, Goto H Wakusawa S. Identification of a novel mutation in the HAMP gene that causes non‐detectable hepcidin molecules in a Japanese male patient with juvenile hemochromatosis. Blood Cells Mol Dis 48(3): 179‐182, 2012.
 75. Hayashi A, Wada Y, Suzuki T, Shimizu A. Studies on familial hypotransferrinemia: Unique clinical course and molecular pathology. Am J Hum Genet 53(1): 201‐213, 1993.
 76. Heinrich HC, Gabbe EE, Oppitz KH, Whang DH, Bender‐Gotze C, Schafer KH, Schroter W, Pfau AA. Absorption of inorganic and food iron in children with heterozygous and homozygous beta‐thalassemia. Z Kinderheilkd 115(1): 1‐22, 1973.
 77. Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA‐based regulatory circuits operated by iron, nitric oxide, and oxidative stress. Proc Natl Acad Sci U S A 93(16): 8175‐8182, 1996.
 78. Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK. Identification of the receptor scavenging hemopexin‐heme complexes. Blood 106(7): 2572‐2579, 2005.
 79. Hwang PK, Greer J. Interaction between hemoglobin subunits in the hemoglobin. Haptoglobin complex. J Biol Chem 255(7): 3038‐3041, 1980.
 80. Iolascon A, Camaschella C, Pospisilova D, Piscopo C, Tchernia G, Beaumont C. Natural history of recessive inheritance of DMT1 mutations. J Pediatr 152(1): 136‐139, 2008.
 81. Isom HC, McDevitt EI, Moon MS. Elevated hepatic iron: A confounding factor in chronic hepatitis C. Biochim Biophys Acta 1790(7): 650‐662, 2009.
 82. Kanda J, Mizumoto C, Kawabata H, Tsuchida H, Tomosugi N, Matsuo K, Uchiyama T. Serum hepcidin level and erythropoietic activity after hematopoietic stem cell transplantation. Haematologica 93(10): 1550‐1554, 2008.
 83. Kaplan J. Mechanisms of cellular iron acquisition: Another iron in the fire. Cell 111(5): 603‐606, 2002.
 84. Kaplan J, Ward DM, De Domenico I. The molecular basis of iron overload disorders and iron‐linked anemias. Int J Hematol 93(1): 14‐20, 2011.
 85. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H Roth MP. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 112(4): 1503‐1509, 2008.
 86. Kawabata H, Fleming RE, Gui D, Moon SY, Saitoh T, O'Kelly J, Umehara Y, Wano Y, Said JW, Koeffler HP. Expression of hepcidin is down‐regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105(1): 376‐381, 2005.
 87. Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koeffler HP. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells. Blood 98(9): 2714‐2719, 2001.
 88. Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D. Time‐course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106(5): 1864‐1866, 2005.
 89. Knutson MD, Oukka M, Koss LM, Aydemir F, Wessling‐Resnick M. Iron release from macrophages after erythrophagocytosis is up‐regulated by ferroportin 1 overexpression and down‐regulated by hepcidin. Proc Natl Acad Sci U S A 102(5): 1324‐1328, 2005.
 90. Koppenol WH. The Haber‐Weiss cycle–70 years later. Redox Rep 6(4): 229‐234, 2001.
 91. Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz‐Knappe P, Adermann K. LEAP‐1, a novel highly disulfide‐bonded human peptide, exhibits antimicrobial activity. FEBS Lett 480(2‐3): 147‐150, 2000.
 92. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK. Identification of the haemoglobin scavenger receptor. Nature 409(6817): 198‐201, 2001.
 93. Kwiatkowski JL. Real‐world use of iron chelators. Hematology Am Soc Hematol Educ Program 2011: 451‐458, 2011.
 94. Lakhal S, Schodel J, Townsend AR, Pugh CW, Ratcliffe PJ, Mole DR. Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia‐inducible factors: New link between hypoxia signaling and iron homeostasis. J Biol Chem 286(6): 4090‐4097, 2011.
 95. Lamb JE, Ray F, Ward JH, Kushner JP, Kaplan J. Internalization and subcellular localization of transferrin and transferrin receptors in HeLa cells. J Biol Chem 258(14): 8751‐8758, 1983.
 96. Lambert LA. Molecular evolution of the transferrin family and associated receptors. Biochim Biophys Acta 1820(3): 244‐255, 2012.
 97. Lambert LA, Perri H, Halbrooks PJ, Mason AB. Evolution of the transferrin family: Conservation of residues associated with iron and anion binding. Comp Biochem Physiol B Biochem Mol Biol 142(2): 129‐141, 2005.
 98. Lambert LA, Perri H, Meehan TJ. Evolution of duplications in the transferrin family of proteins. Comp Biochem Physiol B Biochem Mol Biol 140(1): 11‐25, 2005.
 99. Lasocki S, Millot S, Andrieu V, Letteron P, Pilard N, Muzeau F, Thibaudeau O, Montravers P, Beaumont C. Phlebotomies or erythropoietin injections allow mobilization of iron stores in a mouse model mimicking intensive care anemia. Crit Care Med 36(8): 2388‐2394, 2008.
 100. Latunde‐Dada GO, Simpson RJ, McKie AT. Duodenal cytochrome B expression stimulates iron uptake by human intestinal epithelial cells. J Nutr 138(6): 991‐995, 2008.
 101. Lesbordes‐Brion JC, Viatte L, Bennoun M, Lou DQ, Ramey G, Houbron C, Hamard G, Kahn A, Vaulont S. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 108(4): 1402‐1405, 2006.
 102. Levy JE, Montross LK, Cohen DE, Fleming MD, Andrews NC. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 94(1): 9‐11, 1999.
 103. Li JY, Paragas N, Ned RM, Qiu A, Viltard M, Leete T, Drexler IR, Chen X, Sanna‐Cherchi S, Mohammed F Williams D, Lin CS, Schmidt‐Ott KM, Andrews NC, Barasch J. Scara5 is a ferritin receptor mediating non‐transferrin iron delivery. Dev Cell 16(1): 35‐46, 2009.
 104. Lillie RD. Experiments on the solubility of hemosiderin in acids and other reagents during and after various fixations. Am J Pathol 15(2): 225‐239, 1939.
 105. Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. Zip14 (Slc39a14) mediates non‐transferrin‐bound iron uptake into cells. Proc Natl Acad Sci U S A 103(37): 13612‐13617, 2006.
 106. Lundvall O, Weinfeld A, Lundin P. Iron stores in alcohol abusers. I. Liver iron. Acta Med Scand 185(4): 259‐269, 1969.
 107. Mackenzie B, Garrick MD. Iron Imports. II. Iron uptake at the apical membrane in the intestine. Am J Physiol Gastrointest Liver Physiol 289(6): G981‐986, 2005.
 108. Mastrogiannaki M, Matak P, Mathieu JR, Delga S, Mayeux P, Vaulont S, Peyssonnaux C. Hepatic HIF‐2 down‐regulates hepcidin expression in mice through epo‐mediated increase in erythropoiesis. Haematologica 97(6): 827‐834, 2012.
 109. McKie AT, Barrow D, Latunde‐Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F, Simpson RJ. An iron‐regulated ferric reductase associated with the absorption of dietary iron. Science 291(5509): 1755‐1759, 2001.
 110. McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F Hediger MA, Hentze MW, Simpson RJ. A novel duodenal iron‐regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5(2): 299‐309, 2000.
 111. Meynard D, Kautz L, Darnaud V, Canonne‐Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41(4): 478‐481, 2009.
 112. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF‐kappaB signaling. Cell Res 21(1): 103‐115, 2011.
 113. Muckenthaler MU, Galy B, Hentze MW. Systemic iron homeostasis and the iron‐responsive element/iron‐regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 28197‐213, 2008.
 114. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol 122(2‐3): 78‐86, 2009.
 115. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL‐6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113(9): 1271‐1276, 2004.
 116. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood 105(4): 1803‐1806, 2005.
 117. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704): 2090‐2093, 2004.
 118. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute‐phase protein. Blood 101(7): 2461‐2463, 2003.
 119. 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 U S A 98(15): 8780‐8785, 2001.
 120. 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 U S A 99(7): 4596‐4601, 2002.
 121. Nicolas G, Chauvet C, Viatte L, Danan JL, 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 110(7): 1037‐1044, 2002.
 122. Nicolas G, Viatte L, Lou DQ, Bennoun M, Beaumont C, Kahn A, Andrews NC, Vaulont S. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 34(1): 97‐101, 2003.
 123. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long‐term survival in patients with hereditary hemochromatosis. Gastroenterology 110(4): 1107‐1119, 1996.
 124. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 313(20): 1256‐1262, 1985.
 125. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 115(8): 2180‐2186, 2005.
 126. Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD. Identification of a ferrireductase required for efficient transferrin‐dependent iron uptake in erythroid cells. Nat Genet 37(11): 1264‐1269, 2005.
 127. Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood 108(4): 1388‐1394, 2006.
 128. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population‐based study of the clinical expression of the hemochromatosis gene. N Engl J Med 341(10): 718‐724, 1999.
 129. Osaki S, Johnson DA. Mobilization of liver iron by ferroxidase (ceruloplasmin). J Biol Chem 244(20): 5757‐5758, 1969.
 130. Osaki S, Johnson DA, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 241(12): 2746‐2751, 1966.
 131. Oudit GY, Sun H, Trivieri MG, Koch SE, Dawood F, Ackerley C, Yazdanpanah M, Wilson GJ, Schwartz A, Liu PP Backx PH. L‐type Ca2+ channels provide a major pathway for iron entry into cardiomyocytes in iron‐overload cardiomyopathy. Nat Med 9(9): 1187‐1194, 2003.
 132. Papanikolaou G, Samuels ME, Ludwig EH, MacDonald ML, Franchini PL, Dube MP, Andres L, MacFarlane J, Sakellaropoulos N, Politou M Nemeth E, Thompson J, Risler JK, Zaborowska C, Babakaiff R, Radomski CC, Pape TD, Davidas O, Christakis J, Brissot P, Lockitch G, Ganz T, Hayden MR, Goldberg YP. Mutations in HFE2 cause iron overload in chromosome 1q‐linked juvenile hemochromatosis. Nat Genet 36(1): 77‐82, 2004.
 133. Parrow NL, Gardenghi S, Ramos P, Casu C, Grady RW, Anderson ER, Shah YM, Li H, Ginzburg YZ, Fleming RE Rivella S. Decreased hepcidin expression in murine beta‐thalassemia is associated with suppression of Bmp/Smad signaling. Blood 119(13): 3187‐3189, 2012.
 134. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS. Regulation of iron homeostasis by the hypoxia‐inducible transcription factors (HIFs). J Clin Invest 117(7): 1926‐1932, 2007.
 135. Pietrangelo A, Gualdi R, Casalgrandi G, Geerts A, De Bleser P, Montosi G, Ventura E. Enhanced hepatic collagen type I mRNA expression into fat‐storing cells in a rodent model of hemochromatosis. Hepatology 19(3): 714‐721, 1994.
 136. 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 276(11): 7811‐7819, 2001.
 137. Pinto JP, Ribeiro S, Pontes H, Thowfeequ S, Tosh D, Carvalho F, Porto G. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood 111(12): 5727‐5733, 2008.
 138. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol 35(1): 35‐54, 1998.
 139. Powell LW. Normal human iron storage and its relation to ethanol consumption. Australas Ann Med 15(2): 110‐115, 1966.
 140. Preza GC, Ruchala P, Pinon R, Ramos E, Qiao B, Peralta MA, Sharma S, Waring A, Ganz T, Nemeth E. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 121(12): 4880‐4888, 2011.
 141. Qiao B, Sugianto P, Fung E, Del‐Castillo‐Rueda A, Moran‐Jimenez MJ, Ganz T, Nemeth E. Hepcidin‐induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab 15(6): 918‐924, 2012.
 142. Radisky DC, Kaplan J. Iron in cytosolic ferritin can be recycled through lysosomal degradation in human fibroblasts. Biochem J 336(Pt 1): 201‐205, 1998.
 143. Rajpathak SN, Crandall JP, Wylie‐Rosett J, Kabat GC, Rohan TE, Hu FB. The role of iron in type 2 diabetes in humans. Biochim Biophys Acta 1790(7): 671‐681, 2009.
 144. Ramey G, Deschemin JC, Durel B, Canonne‐Hergaux F, Nicolas G, Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica 95(3): 501‐504, 2010.
 145. Ramm GA, Ruddell RG. Hepatotoxicity of iron overload: Mechanisms of iron‐induced hepatic fibrogenesis. Semin Liver Dis 25(4): 433‐449, 2005.
 146. Remacle J, Raes M, Toussaint O, Renard P, Rao G. Low levels of reactive oxygen species as modulators of cell function. Mutat Res 316(3): 103‐122, 1995.
 147. Rivera S, Ganz T. Animal models of anemia of inflammation. Semin Hematol 46(4): 351‐357, 2009.
 148. Ross SL, Tran L, Winters A, Lee KJ, Plewa C, Foltz I, King C, Miranda LP, Allen J, Beckman H Cooke KS, Moody G, Sasu BJ, Nemeth E, Ganz T, Molineux G, Arvedson TL. Molecular mechanism of hepcidin‐mediated ferroportin internalization requires ferroportin lysines, not tyrosines or JAK‐STAT. Cell Metab 15(6): 905‐917, 2012.
 149. Rous P. Urinary siderosis: Hemosiderin granules in the urine as an aid in the diagnosis of pernicious anemia, hemochromatosis, and other diseases causing siderosis of the kidney. J Exp Med 28(5): 645‐658, 1918.
 150. Roy CN, Custodio AO, de Graaf J, Schneider S, Akpan I, Montross LK, Sanchez M, Gaudino A, Hentze MW, Andrews NC Muckenthaler MU. An Hfe‐dependent pathway mediates hyposideremia in response to lipopolysaccharide‐induced inflammation in mice. Nat Genet 36(5): 481‐485, 2004.
 151. Sakaida I, Hironaka K, Uchida K, Okita K. Iron chelator deferoxamine reduces preneoplastic lesions in liver induced by choline‐deficient L‐amino acid‐defined diet in rats. Dig Dis Sci 44(3): 560‐569, 1999.
 152. Santos PC, Krieger JE, Pereira AC. Molecular diagnostic and pathogenesis of hereditary hemochromatosis. Int J Mol Sci 13(2): 1497‐1511, 2012.
 153. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe‐dependent regulation of hepcidin expression. Cell Metab 7(3): 205‐214, 2008.
 154. Shindo M, Torimoto Y, Saito H, Motomura W, Ikuta K, Sato K, Fujimoto Y, Kohgo Y. Functional role of DMT1 in transferrin‐independent iron uptake by human hepatocyte and hepatocellular carcinoma cell, HLF. Hepatol Res 35(3): 152‐162, 2006.
 155. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase‐2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab 8(6): 502‐511, 2008.
 156. Skillings JR, Rogers‐Melamed I, Nabholtz JM, Sawka C, Gwadry‐Sridhar F, Moquin JP, Rubinger M, Ganguly P, Burnell M, Shustik C Dryer D, McLaughlin M, White D. An epidemiological review of red cell transfusions in cancer chemotherapy. Cancer Prev Control 3(3): 207‐212, 1999.
 157. Skinner MK, Griswold MD. Secretion of testicular transferrin by cultured Sertoli cells is regulated by hormones and retinoids. Biol Reprod 27(1): 211‐221, 1982.
 158. Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K. Down‐regulation of hepcidin resulting from long‐term treatment with an anti‐IL‐6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood 116(18): 3627‐3634, 2010.
 159. Sposi NM, Cianetti L, Tritarelli E, Pelosi E, Militi S, Barberi T, Gabbianelli M, Saulle E, Kuhn L, Peschle C Testa U. Mechanisms of differential transferrin receptor expression in normal hematopoiesis. EurJ Biochem 267(23): 6762‐6774, 2000.
 160. Stal P, Broome U, Scheynius A, Befrits R, Hultcrantz R. Kupffer cell iron overload induces intercellular adhesion molecule‐1 expression on hepatocytes in genetic hemochromatosis. Hepatology 21(5): 1308‐1316, 1995.
 161. Steinberg MH, Forget BG, Higgs DR, Nagel RL. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Cambridge, United Kingdom: Cambridge University Press, 2001.
 162. Strohmeyer G, Niederau C, Stremmel W. Survival and causes of death in hemochromatosis. Observations in 163 patients. Ann N Y Acad Sci 526: 245‐257, 1988.
 163. Sun CC, Vaja V, Babitt JL, Lin HY. Targeting the hepcidin‐ferroportin axis to develop new treatment strategies for anemia of chronic disease and anemia of inflammation. Am J Hematol 87(4): 392‐400, 2012.
 164. Taher A, Hershko C, Cappellini MD. Iron overload in thalassaemia intermedia: Reassessment of iron chelation strategies. Br J Haematol 147(5): 634‐640, 2009.
 165. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 13(9): 1096‐1101, 2007.
 166. Tanno T, Porayette P, Sripichai O, Noh SJ, Byrnes C, Bhupatiraju A, Lee YT, Goodnough JB, Harandi O, Ganz T Paulson RF, Miller JL. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood 114(1): 181‐186, 2009.
 167. Theil EC. Ferritin: Structure, gene regulation, and cellular function in animals, plants, and microorganisms. Annu Rev Biochem 56: 289‐315, 1987.
 168. Tolosano E, Altruda F. Hemopexin: Structure, function, and regulation. DNA Cell Biol 21(4): 297‐306, 2002.
 169. Torti SV, Kwak EL, Miller SC, Miller LL, Ringold GM, Myambo KB, Young AP, Torti FM. The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor‐inducible gene. J Biol Chem 263(25): 12638‐12644, 1988.
 170. Toth I, Yuan L, Rogers JT, Boyce H, Bridges KR. Hypoxia alters iron‐regulatory protein‐1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells. J Biol Chem 274(7): 4467‐4473, 1999.
 171. Trenor CC, III, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood 96(3): 1113‐1118, 2000.
 172. Trombini P, Paolini V, Pelucchi S, Mariani R, Nemeth E, Ganz T, Piperno A. Hepcidin response to acute iron intake and chronic iron loading in dysmetabolic iron overload syndrome. Liver Int 31(7): 994‐1000, 2011.
 173. Tsuji Y, Ayaki H, Whitman SP, Morrow CS, Torti SV, Torti FM. Coordinate transcriptional and translational regulation of ferritin in response to oxidative stress. Mol Cell Biol 20(16): 5818‐5827, 2000.
 174. Valenti L, Dongiovanni P, Fracanzani AL, Santorelli G, Fatta E, Bertelli C, Taioli E, Fiorelli G, Fargion S. Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis. Dig Liver Dis 35(3): 172‐178, 2003.
 175. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis 40(1): 132‐138, 2008.
 176. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109(1): 353‐358, 2007.
 177. Viatte L, Nicolas G, Lou DQ, Bennoun M, Lesbordes‐Brion JC, Canonne‐Hergaux F, Schonig K, Bujard H, Kahn A, Andrews NC Vaulont S. Chronic hepcidin induction causes hyposideremia and alters the pattern of cellular iron accumulation in hemochromatotic mice. Blood 107(7): 2952‐2958, 2006.
 178. Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res 55(6): 667‐674, 2006.
 179. Volke M, Gale DP, Maegdefrau U, Schley G, Klanke B, Bosserhoff AK, Maxwell PH, Eckardt KU, Warnecke C. Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia‐inducible factors. PLoS One 4(11): e7875, 2009.
 180. Vujic Spasic M, Kiss J, Herrmann T, Galy B, Martinache S, Stolte J, Grone HJ, Stremmel W, Hentze MW, Muckenthaler MU. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab 7(2): 173‐178, 2008.
 181. Vujic Spasic M, Kiss J, Herrmann T, Kessler R, Stolte J, Galy B, Rathkolb B, Wolf E, Stremmel W, Hentze MW Muckenthaler MU. Physiologic systemic iron metabolism in mice deficient for duodenal Hfe. Blood 109(10): 4511‐4517, 2007.
 182. Wallace DF, Summerville L, Subramaniam VN. Targeted disruption of the hepatic transferrin receptor 2 gene in mice leads to iron overload. Gastroenterology 132(1): 301‐310, 2007.
 183. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L Deng CX. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2(6): 399‐409, 2005.
 184. Wei Y, Miller SC, Tsuji Y, Torti SV, Torti FM. Interleukin 1 induces ferritin heavy chain in human muscle cells. Biochem Biophys Res Commun 169(1): 289‐296, 1990.
 185. Wrighting DM, Andrews NC. Interleukin‐6 induces hepcidin expression through STAT3. Blood 108(9): 3204‐3209, 2006.
 186. Yang B, Kirby S, Lewis J, Detloff PJ, Maeda N, Smithies O. A mouse model for beta 0‐thalassemia. Proc Natl Acad Sci U S A 92(25): 11608‐11612, 1995.
 187. 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 9(3): 267‐272, 1995.
 188. Zhang AS, Gao J, Koeberl DD, Enns CA. The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein‐6 and hepcidin expression in vivo. J Biol Chem 285(22): 16416‐16423, 2010.
 189. Zhang Z, Zhang F, An P, Guo X, Shen Y, Tao Y, Wu Q, Zhang Y, Yu Y, Ning B Nie G, Knutson MD, Anderson GJ, Wang F. Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses. Blood 118(7): 1912‐1922, 2011.
 190. Zhang Z, Zhang F, Guo X, An P, Tao Y, Wang F. Ferroportin1 in hepatocytes and macrophages is required for the efficient mobilization of body iron stores. Hepatology 2012 [Epub ahead of print].
 191. Zhao N, Gao J, Enns CA, Knutson MD. ZRT/IRT‐like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J Biol Chem 285(42): 32141‐32150, 2010.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Erik R. Anderson, Yatrik M. Shah. Iron Homeostasis in the Liver. Compr Physiol 2013, 3: 315-330. doi: 10.1002/cphy.c120016