Iron Homeostasis, Hepatocellular Injury, and Fibrogenesis in Hemochromatosis: The Role of Inflammation in a Noninflammatory Liver Disease

ABSTRACT

Iron is a crucially important element in normal cellular function and thus the regulation of iron homeostasis is tightly controlled. When this regulation is disrupted, for instance in hereditary hemochromatosis, abnormal intestinal absorption of iron leads to cellular toxicity, tissue injury, and organ fibrosis via the deposition of this iron in parenchymal cells of a number of different organs such as the heart, pancreas, and liver. Iron-generated oxyradicals contribute to the peroxidation of lipid membranes leading to organelle fragility and cellular toxicity. This process is thought to contribute to hepatocellular necrosis and/or apoptosis in the liver with the subsequent activation of hepatic stellate cells and the development of hepatic fibrosis and cirrhosis. Understanding the processes associated with normal iron homeostasis is crucially important as this will ultimately provide clues as to how altered iron uptake and delivery leads to tissue injury and organ dysfunction in diseases of disordered iron metabolism. This review highlights recent advances in identifying major regulators associated with hepatic iron homeostasis and examines the potential mechanisms involved in the development of iron overload-induced hepatic injury and fibrogenesis.

KEYWORDS

Iron - inflammation - hepcidin - hepatic stellate cell - hepatic fibrosis - hemochromatosis

REFERENCES

• 1 Anderson G J. Things that go BMP in the liver: bone morphogenetic protein 6 and the control of body iron homeostasis.  Hepatology. 2009;  50 316-319
• 2 Ramm G A, Ruddell R G. Hepatotoxicity of iron overload: mechanisms of iron-induced hepatic fibrogenesis.  Semin Liver Dis. 2005;  25 433-449
• 3 Cullen L M, Anderson G J, Ramm G A, Jazwinska E C, Powell L W. Genetics of hemochromatosis.  Annu Rev Med. 1999;  50 87-98
• 4 Anderson G J, Frazer D M. Hepatic iron metabolism.  Semin Liver Dis. 2005;  25 420-432
• 5 Viatte L, Vaulont S. Hepcidin, the iron watcher.  Biochimie. 2009;  91 1223-1228
• 6 Shayeghi M, Latunde-Dada G O, Oakhill J S et al.. Identification of an intestinal heme transporter.  Cell. 2005;  122 789-801
• 7 Donovan A, Lima C A, Pinkus J L et al.. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis.  Cell Metab. 2005;  1 191-200
• 8 Hahn P F, Bale W F, Ross J F, Balfour W M, Whipple G H. Radioactive iron absorption by gastro-intestinal tract: influence of anemia, anoxia, and antecedent feeding distribution in growing dogs.  J Exp Med. 1943;  78 169-188
• 9 Shah Y M, Matsubara T, Ito S, Yim S H, Gonzalez F J. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency.  Cell Metab. 2009;  9 152-164
• 10 Nemeth E, Tuttle M S, Powelson J et al.. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.  Science. 2004;  306 2090-2093
• 11 Krause A, Neitz S, Mägert H J et al.. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.  FEBS Lett. 2000;  480 147-150
• 12 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
• 13 Nicolas G, Bennoun M, Devaux I et al.. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.  Proc Natl Acad Sci U S A. 2001;  98 8780-8785
• 14 Nicolas G, Bennoun M, Porteu A et al.. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.  Proc Natl Acad Sci U S A. 2002;  99 4596-4601
• 15 De Domenico I, Ward D M, Langelier C et al.. The molecular mechanism of hepcidin-mediated ferroportin down-regulation.  Mol Biol Cell. 2007;  18 2569-2578
• 16 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
• 17 De Domenico I, Nemeth E, Nelson J M et al.. The hepcidin-binding site on ferroportin is evolutionarily conserved.  Cell Metab. 2008;  8 146-156
• 18 Kondo H, Saito K, Grasso J P, Aisen P. Iron metabolism in the erythrophagocytosing Kupffer cell.  Hepatology. 1988;  8 32-38
• 19 De Domenico I, Ward D M, Musci G, Kaplan J. Iron overload due to mutations in ferroportin.  Haematologica. 2006;  91 92-95
• 20 Wallace D F, Clark R M, Harley H A, Subramaniam V N. Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis.  J Hepatol. 2004;  40 710-713
• 21 Harrison P M, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation.  Biochim Biophys Acta. 1996;  1275 161-203
• 22 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 U S A. 1999;  96 10812-10817
• 23 Texel S J, Xu X, Harris Z L. Ceruloplasmin in neurodegenerative diseases.  Biochem Soc Trans. 2008;  36(Pt 6) 1277-1281
• 24 Cherukuri S, Potla R, Sarkar J, Nurko S, Harris Z L, Fox P L. Unexpected role of ceruloplasmin in intestinal iron absorption.  Cell Metab. 2005;  2 309-319
• 25 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
• 26 Kulaksiz H, Theilig F, Bachmann S et al.. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney.  J Endocrinol. 2005;  184 361-370
• 27 Bekri S, Gual P, Anty R et al.. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH.  Gastroenterology. 2006;  131 788-796
• 28 Nguyen N B, Callaghan K D, Ghio A J, Haile D J, Yang F. Hepcidin expression and iron transport in alveolar macrophages.  Am J Physiol Lung Cell Mol Physiol. 2006;  291 L417-L425
• 29 Kulaksiz H, Gehrke S G, Janetzko A et al.. Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia.  Gut. 2004;  53 735-743
• 30 Schranz M, Bakry R, Creus M, Bonn G, Vogel W, Zoller H. Activation and inactivation of the iron hormone hepcidin: biochemical characterization of prohepcidin cleavage and sequential degradation to N-terminally truncated hepcidin isoforms.  Blood Cells Mol Dis. 2009;  43 169-179
• 31 Vujić Spasić M, Kiss J, Herrmann T et al.. Hfe acts in hepatocytes to prevent hemochromatosis.  Cell Metab. 2008;  7 173-178
• 32 Schmidt P J, Toran P T, Giannetti A M, Bjorkman P J, Andrews N C. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression.  Cell Metab. 2008;  7 205-214
• 33 Johnson M B, Chen J, Murchison N, Green F A, Enns C A. Transferrin receptor 2: evidence for ligand-induced stabilization and redirection to a recycling pathway.  Mol Biol Cell. 2007;  18 743-754
• 34 Gao J, Chen J, Kramer M, Tsukamoto H, Zhang A S, Enns C A. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression.  Cell Metab. 2009;  9 217-227
• 35 Feder J N, Gnirke A, Thomas W et al.. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.  Nat Genet. 1996;  13 399-408
• 36 Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis.  Blood. 2005;  105 1803-1806
• 37 Bridle K R, Frazer D M, Wilkins S J et al.. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.  Lancet. 2003;  361 669-673
• 38 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 U S A. 2006;  103 10289-10293
• 39 Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth M P. Lack of the bone morphogenetic protein BMP6 induces massive iron overload.  Nat Genet. 2009;  41 478-481
• 40 Andriopoulos Jr B, Corradini E, Xia Y et al.. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism.  Nat Genet. 2009;  41 482-487
• 41 Kautz L, Meynard D, Monnier A et al.. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver.  Blood. 2008;  112 1503-1509
• 42 Ebisawa T, Tada K, Kitajima I et al.. Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation.  J Cell Sci. 1999;  112(Pt 20) 3519-3527
• 43 Babitt J L, Huang F W, Wrighting D M et al.. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression.  Nat Genet. 2006;  38 531-539
• 44 Wallace D F, Dixon J L, Ramm G A, Anderson G J, Powell L W, Subramaniam N. Hemojuvelin (HJV)-associated hemochromatosis: analysis of HJV and HFE mutations and iron overload in three families.  Haematologica. 2005;  90 254-255
• 45 Babitt J L, Huang F W, Xia Y, Sidis Y, Andrews N C, Lin H Y. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance.  J Clin Invest. 2007;  117 1933-1939
• 46 Lin L, Nemeth E, Goodnough J B, Thapa D R, Gabayan V, Ganz T. Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site.  Blood Cells Mol Dis. 2008;  40 122-131
• 47 Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze M W, Muckenthaler M U. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD.  J Mol Med. 2009;  87 471-480
• 48 Truksa J, Lee P, Beutler E. Two BMP responsive elements, STAT, and bZIP/HNF4/COUP motifs of the hepcidin promoter are critical for BMP, SMAD1, and HJV responsiveness.  Blood. 2009;  113 688-695
• 49 Wang R H, Li C, Xu X et al.. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression.  Cell Metab. 2005;  2 399-409
• 50 Arndt S, Maegdefrau U, Dorn C et al.. Iron-induced expression of BMP6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo.  Gastroenterology. 2010;  138 372-382
• 51 Knittel T, Fellmer P, Müller L, Ramadori G. Bone morphogenetic protein-6 is expressed in nonparenchymal liver cells and upregulated by transforming growth factor-beta 1.  Exp Cell Res. 1997;  232 263-269
• 52 Du X, She E, Gelbart T et al.. The serine protease TMPRSS6 is required to sense iron deficiency.  Science. 2008;  320 1088-1092
• 53 Zhang A S, Yang F, Meyer K et al.. Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane.  J Biol Chem. 2008;  283 17494-17502
• 54 Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin.  Cell Metab. 2008;  8 502-511
• 55 Velasco G, Cal S, Quesada V, Sánchez L M, López-Otín C. Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins.  J Biol Chem. 2002;  277 37637-37646
• 56 Zhang A S, Anderson S A, Meyers K R, Hernandez C, Eisenstein R S, Enns C A. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin.  J Biol Chem. 2007;  282 12547-12556
• 57 Zhang A S, Yang F, Wang J, Tsukamoto H, Enns C A. Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression.  J Biol Chem. 2009;  284 22580-22589
• 58 Xia Y, Babitt J L, Sidis Y, Chung R T, Lin H Y. Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin.  Blood. 2008;  111 5195-5204
• 59 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
• 60 Verga Falzacappa M V, Vujic Spasic M, Kessler R, Stolte J, Hentze M W, Muckenthaler M U. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation.  Blood. 2007;  109 353-358
• 61 Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6.  Proc Natl Acad Sci U S A. 2005;  102 1906-1910
• 62 Ruddell R G, Hoang-Le D, Barwood J M et al.. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells.  Hepatology. 2009;  49 887-900
• 63 Waris G, Tardif K D, Siddiqui A. Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3.  Biochem Pharmacol. 2002;  64 1425-1430
• 64 Zhao L, Ackerman S L. Endoplasmic reticulum stress in health and disease.  Curr Opin Cell Biol. 2006;  18 444-452
• 65 Zhang K, Shen X, Wu J et al.. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response.  Cell. 2006;  124 587-599
• 66 Vecchi C, Montosi G, Zhang K et al.. ER stress controls iron metabolism through induction of hepcidin.  Science. 2009;  325 877-880
• 67 Philippe M A, Ruddell R G, Ramm G A. Role of iron in hepatic fibrosis: one piece in the puzzle.  World J Gastroenterol. 2007;  13 4746-4754
• 68 Videla L A, Fernández V, Tapia G, Varela P. Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells.  Biometals. 2003;  16 103-111
• 69 Britton R S, Leicester K L, Bacon B R. Iron toxicity and chelation therapy.  Int J Hematol. 2002;  76 219-228
• 70 Pietrangelo A. Iron-induced oxidant stress in alcoholic liver fibrogenesis.  Alcohol. 2003;  30 121-129
• 71 Wu G, Fang Y Z, Yang S, Lupton J R, Turner N D. Glutathione metabolism and its implications for health.  J Nutr. 2004;  134 489-492
• 72 Sies H. Oxidative stress: from basic research to clinical application.  Am J Med. 1991;  91(3C) 31S-38S
• 73 Iacopetta B J, Morgan E H, Yeoh G C. Receptor-mediated endocytosis of transferrin by developing erythroid cells from the fetal rat liver.  J Histochem Cytochem. 1983;  31 336-344
• 74 Ramm G A, Powell L W, Halliday J W. Pathways of intracellular trafficking and release of ferritin by the liver in vivo: the effect of chloroquine and cytochalasin D.  Hepatology. 1994;  19 504-513
• 75 O'Connell M J, Ward R J, Baum H, Peters T J. The role of iron in ferritin- and haemosiderin-mediated lipid peroxidation in liposomes.  Biochem J. 1985;  229 135-139
• 76 Bacon B R, O'Neill R, Britton R S. Hepatic mitochondrial energy production in rats with chronic iron overload.  Gastroenterology. 1993;  105 1134-1140
• 77 Britton R S, O'Neill R, Bacon B R. Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes [corrected].  Gastroenterology. 1991;  101 806-811
• 78 Masini A, Ceccarelli D, Trenti T, Corongiu F P, Muscatello U. Perturbation in liver mitochondrial Ca2 + homeostasis in experimental iron overload: a possible factor in cell injury.  Biochim Biophys Acta. 1989;  1014 133-140
• 79 Walter P B, Knutson M D, Paler-Martinez A et al.. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats.  Proc Natl Acad Sci U S A. 2002;  99 2264-2269
• 80 García N, García J J, Correa F, Chávez E. The permeability transition pore as a pathway for the release of mitochondrial DNA.  Life Sci. 2005;  76 2873-2880
• 81 Rauen U, Petrat F, Sustmann R, de Groot H. Iron-induced mitochondrial permeability transition in cultured hepatocytes.  J Hepatol. 2004;  40 607-615
• 82 Kim J S, Qian T, Lemasters J J. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes.  Gastroenterology. 2003;  124 494-503
• 83 Uchiyama A, Kim J S, Kon K et al.. Translocation of iron from lysosomes into mitochondria is a key event during oxidative stress-induced hepatocellular injury.  Hepatology. 2008;  48 1644-1654
• 84 Lawless M W, Mankan A K, Norris S. Hereditary hemochromatosis should be considered a conformational disorder.  Med Hypotheses. 2008;  70 783-784
• 85 de Almeida S F, de Sousa M. The unfolded protein response in hereditary haemochromatosis.  J Cell Mol Med. 2008;  12 421-434
• 86 Lin E, Adams P C. Biochemical liver profile in hemochromatosis. A survey of 100 patients.  J Clin Gastroenterol. 1991;  13 316-320
• 87 Adams P C. Is there a threshold of hepatic iron concentration that leads to cirrhosis in C282Y hemochromatosis?.  Am J Gastroenterol. 2001;  96 567-569
• 88 Powell L W, Dixon J L, Ramm G A et al.. Screening for hemochromatosis in asymptomatic subjects with or without a family history.  Arch Intern Med. 2006;  166 294-301
• 89 Guyader D, Jacquelinet C, Moirand R et al.. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis.  Gastroenterology. 1998;  115 929-936
• 90 Beaton M, Guyader D, Deugnier Y, Moirand R, Chakrabarti S, Adams P. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis.  Hepatology. 2002;  36 673-678
• 91 Crawford D H, Murphy T L, Ramm L E et al.. Serum hyaluronic acid with serum ferritin accurately predicts cirrhosis and reduces the need for liver biopsy in C282Y hemochromatosis.  Hepatology. 2009;  49 418-425
• 92 Nair J, Carmichael P L, Fernando R C, Phillips D H, Strain A J, Bartsch H. Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson's disease and primary hemochromatosis.  Cancer Epidemiol Biomarkers Prev. 1998;  7 435-440
• 93 Hussain S P, Raja K, Amstad P A et al.. Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases.  Proc Natl Acad Sci U S A. 2000;  97 12770-12775
• 94 Niederau C, Fischer R, Pürschel A, Stremmel W, Häussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis.  Gastroenterology. 1996;  110 1107-1119
• 95 Lehmann U, Wingen L U, Brakensiek K et al.. Epigenetic defects of hepatocellular carcinoma are already found in non-neoplastic liver cells from patients with hereditary haemochromatosis.  Hum Mol Genet. 2007;  16 1335-1342
• 96 Powell L, Jazwinska E, Halliday J. Primary iron overload. In: Brock J, Halliday J, Pippard M, Powell L Iron Metabolism in Health and Disease. Philadelphia, PA; WB Saunders & Co., Ltd. 1994: 227-270
• 97 Eisenbach C, Gehrke S G, Stremmel W. Iron, the HFE gene, and hepatitis C.  Clin Liver Dis. 2004;  8 775-785 vii-viii
• 98 Fletcher L M, Dixon J L, Purdie D M, Powell L W, Crawford D H. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology. 2002;  122 281-289
• 99 Wood M J, Powell L W, Ramm G A. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis.  Blood. 2008;  111 4456-4462
• 100 Stickel F, Osterreicher C H, Datz C et al.. Prediction of progression to cirrhosis by a glutathione S-transferase P1 polymorphism in subjects with hereditary hemochromatosis.  Arch Intern Med. 2005;  165 1835-1840
• 101 Osterreicher C H, Datz C, Stickel F et al.. Association of myeloperoxidase promotor polymorphism with cirrhosis in patients with hereditary hemochromatosis.  J Hepatol. 2005;  42 914-919
• 102 Krayenbuehl P A, Hersberger M, Truninger K et al.. Toll-like receptor 4 gene polymorphism modulates phenotypic expression in patients with hereditary hemochromatosis.  Eur J Gastroenterol Hepatol. 2009;  , [Epub ahead of print]
• 103 Friedman S L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.  Physiol Rev. 2008;  88 125-172
• 104 Neuschwander-Tetri B A, Bridle K R, Wells L D, Marcu M, Ramm G A. Repetitive acute pancreatic injury in the mouse induces procollagen alpha1(I) expression colocalized to pancreatic stellate cells.  Lab Invest. 2000;  80 143-150
• 105 Schnaper H W, Hayashida T, Hubchak S C, Poncelet A C. TGF-beta signal transduction and mesangial cell fibrogenesis.  Am J Physiol Renal Physiol. 2003;  284 F243-F252
• 106 Forbes S J, Russo F P, Rey V et al.. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis.  Gastroenterology. 2004;  126 955-963
• 107 Kisseleva T, Uchinami H, Feirt N et al.. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis.  J Hepatol. 2006;  45 429-438
• 108 Omenetti A, Porrello A, Jung Y et al.. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans.  J Clin Invest. 2008;  118 3331-3342
• 109 Ooi L P, Crawford D H, Gotley D C et al.. Evidence that “myofibroblast-like” cells are the cellular source of capsular collagen in hepatocellular carcinoma.  J Hepatol. 1997;  26 798-807
• 110 Bridle K R, Crawford D H, Powell L W, Ramm G A. Role of myofibroblasts in tumour encapsulation of hepatocellular carcinoma in haemochromatosis.  Liver. 2001;  21 96-104
• 111 Ramm G A, Crawford D H, Powell L W, Walker N I, Fletcher L M, Halliday J W. Hepatic stellate cell activation in genetic haemochromatosis. Lobular distribution, effect of increasing hepatic iron and response to phlebotomy.  J Hepatol. 1997;  26 584-592
• 112 Guido M, Rugge M, Leandro G, Fiel I M, Thung S N. Hepatic stellate cell immunodetection and cirrhotic evolution of viral hepatitis in liver allografts.  Hepatology. 1997;  26 310-314
• 113 Houglum K, Bedossa P, Chojkier M. TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload.  Am J Physiol. 1994;  267(5 Pt 1) G908-G913
• 114 Pietrangelo A, Gualdi R, Casalgrandi G et al.. Enhanced hepatic collagen type I mRNA expression into fat-storing cells in a rodent model of hemochromatosis.  Hepatology. 1994;  19 714-721
• 115 Ramm G A, Li S C, Li L et al.. Chronic iron overload causes activation of rat lipocytes in vivo.  Am J Physiol. 1995;  268(3 Pt 1) G451-G458
• 116 Zhao M, Laissue J A, Zimmermann A. Hepatocyte apoptosis in hepatic iron overload diseases.  Histol Histopathol. 1997;  12 367-374
• 117 Moerman P, Pauwels P, Vandenberghe K et al.. Neonatal haemochromatosis.  Histopathology. 1990;  17 345-351
• 118 Houglum K, Filip M, Witztum J L, Chojkier M. Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload.  J Clin Invest. 1990;  86 1991-1998
• 119 Houglum K, Ramm G A, Crawford D H, Witztum J L, Powell L W, Chojkier M. Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis.  Hepatology. 1997;  26 605-610
• 120 Dai J, Huang C, Wu J, Yang C, Frenkel K, Huang X. Iron-induced interleukin-6 gene expression: possible mediation through the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways.  Toxicology. 2004;  203 199-209
• 121 Hagen K, Eckes K, Melefors O, Hultcrantz R. Iron overload decreases the protective effect of tumour necrosis factor-alpha on rat hepatocytes exposed to oxidative stress.  Scand J Gastroenterol. 2002;  37 725-731
• 122 Hagen K, Zhu C, Melefors O, Hultcrantz R. Susceptibility of cultured rat hepatocytes to oxidative stress by peroxides and iron. The extracellular matrix affects the toxicity of tert-butyl hydroperoxide.  Int J Biochem Cell Biol. 1999;  31 499-508
• 123 Stål P, Broomé U, Scheynius A, Befrits R, Hultcrantz R. Kupffer cell iron overload induces intercellular adhesion molecule-1 expression on hepatocytes in genetic hemochromatosis.  Hepatology. 1995;  21 1308-1316
• 124 Wallace D F, Subramaniam V N. Non-HFE haemochromatosis.  World J Gastroenterol. 2007;  13 4690-4698
• 125 She H, Xiong S, Lin M, Zandi E, Giulivi C, Tsukamoto H. Iron activates NF-kappaB in Kupffer cells.  Am J Physiol Gastrointest Liver Physiol. 2002;  283 G719-G726
• 126 Xiong S, She H, Sung C K, Tsukamoto H. Iron-dependent activation of NF-kappaB in Kupffer cells: a priming mechanism for alcoholic liver disease.  Alcohol. 2003;  30 107-113
• 127 Tsukamoto H, Rippe R, Niemelä O, Lin M. Roles of oxidative stress in activation of Kupffer and Ito cells in liver fibrogenesis.  J Gastroenterol Hepatol. 1995;  10(Suppl 1) S50-S53
• 128 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
• 129 Oudar O, Moreau A, Feldmann G, Scoazec J Y. Expression and regulation of intercellular adhesion molecule-1 (ICAM-1) in organotypic cultures of rat liver tissue.  J Hepatol. 1998;  29 901-909
• 130 Selzner N, Selzner M, Odermatt B, Tian Y, Van Rooijen N, Clavien P A. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice.  Gastroenterology. 2003;  124 692-700
• 131 Canbay A, Feldstein A E, Higuchi H et al.. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression.  Hepatology. 2003;  38 1188-1198
• 132 Lowes K N, Brennan B A, Yeoh G C, Olynyk J K. Oval cell numbers in human chronic liver diseases are directly related to disease severity.  Am J Pathol. 1999;  154 537-541
• 133 Smith P G, Yeoh G C. Chronic iron overload in rats induces oval cells in the liver.  Am J Pathol. 1996;  149 389-398
• 134 Ruddell R G, Knight B, Tirnitz-Parker J E et al.. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury.  Hepatology. 2009;  49 227-239
• 135 MacDonald G A, Bridle K R, Ward P J et al.. Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3.  J Gastroenterol Hepatol. 2001;  16 599-606
• 136 Parola M, Pinzani M, Casini A et al.. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells.  Biochem Biophys Res Commun. 1993;  194 1044-1050
• 137 Bedossa P, Houglum K, Trautwein C, Holstege A, Chojkier M. Stimulation of collagen alpha 1(I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis?.  Hepatology. 1994;  19 1262-1271
• 138 Montosi G, Garuti C, Martinelli S, Pietrangelo A. Hepatic stellate cells are not subjected to oxidant stress during iron-induced fibrogenesis in rodents.  Hepatology. 1998;  27 1611-1622
• 139 Olynyk J K, Khan N A, Ramm G A et al.. Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells.  J Gastroenterol Hepatol. 2002;  17 785-790
• 140 Maher J J, Tzagarakis C, Giménez A. Malondialdehyde stimulates collagen production by hepatic lipocytes only upon activation in primary culture.  Alcohol Alcohol. 1994;  29 605-610
• 141 Apte M. Oxidative stress: does it “initiate” hepatic stellate cell activation or only “perpetuate” the process?.  J Gastroenterol Hepatol. 2002;  17 1045-1048
• 142 Recalcati S, Invernizzi P, Arosio P, Cairo G. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity.  J Autoimmun. 2008;  30 84-89
• 143 Arosio P, Ingrassia R, Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more.  Biochim Biophys Acta. 2009;  1790 589-599
• 144 Leggett B A, Fletcher L M, Ramm G A, Powell L W, Halliday J W. Differential regulation of ferritin H and L subunit mRNA during inflammation and long-term iron overload.  J Gastroenterol Hepatol. 1993;  8 21-27
• 145 Theil E C, Goss D J. Living with iron (and oxygen): questions and answers about iron homeostasis.  Chem Rev. 2009;  109 4568-4579
• 146 Ramm G A, Britton R S, O'Neill R, Bacon B R. Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes.  J Clin Invest. 1994;  94 9-15
• 147 Chen T T, Li L, Chung D H et al.. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis.  J Exp Med. 2005;  202 955-965
• 148 Li J Y, Paragas N, Ned R M et al.. Scara5 is a ferritin receptor mediating non-transferrin iron delivery.  Dev Cell. 2009;  16 35-46
• 149 Todorich B, Zhang X, Slagle-Webb B, Seaman W E, Connor J R. Tim-2 is the receptor for H-ferritin on oligodendrocytes.  J Neurochem. 2008;  107 1495-1505
• 150 Adams P C, Powell L W, Halliday J W. Isolation of a human hepatic ferritin receptor.  Hepatology. 1988;  8 719-721
• 151 Bridle K R, Crawford D H, Ramm G A. Identification and characterization of the hepatic stellate cell transferrin receptor.  Am J Pathol. 2003;  162 1661-1667
• 152 Bridle K R, Crawford D H, Fletcher L M, Smith J L, Powell L W, Ramm G A. Evidence for a sub-morphological inflammatory process in the liver in haemochromatosis.  J Hepatol. 2003;  38 426-433
• 153 Deugnier Y M, Loréal O, Turlin B et al.. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations.  Gastroenterology. 1992;  102 2050-2059
• 154 Arthur M J. Iron overload and liver fibrosis.  J Gastroenterol Hepatol. 1996;  11 1124-1129
• 155 Roberts F D, Charalambous P, Fletcher L, Powell L W, Halliday J W. Effect of chronic iron overload on procollagen gene expression.  Hepatology. 1993;  18 590-595
• 156 Parkes J G, Templeton D M. Modulation of stellate cell proliferation and gene expression by rat hepatocytes: effect of toxic iron overload.  Toxicol Lett. 2003;  144 225-233
• 157 Reimão R, Porto G, de Sousa M. Stability of CD4/CD8 ratios in man: new correlation between CD4/CD8 profiles and iron overload in idiopathic haemochromatosis patients.  C R Acad Sci III. 1991;  313 481-487
• 158 Porto G, Vicente C, Teixeira M A et al.. Relative impact of HLA phenotype and CD4-CD8 ratios on the clinical expression of hemochromatosis.  Hepatology. 1997;  25 397-402
• 159 Cardoso E M, Hagen K, de Sousa M, Hultcrantz R. Hepatic damage in C282Y homozygotes relates to low numbers of CD8 + cells in the liver lobuli.  Eur J Clin Invest. 2001;  31 45-53
• 160 Fabio G, Zarantonello M, Mocellin C et al.. Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients.  J Hepatol. 2002;  37 753-761
• 161 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
• 162 Arosa F A, Oliveira L, Porto G et al.. Anomalies of the CD8 + T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8 + CD28- T cells.  Clin Exp Immunol. 1997;  107 548-554
• 163 Cruz E, Whittington C, Krikler S H et al.. A new 500 kb haplotype associated with high CD8 + T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis.  BMC Med Genet. 2008;  9 97