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Oxidative Stress and Hepatic Iron Overload

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Studies on Hepatic Disorders

Abstract

Iron is an essential nutrient, playing a crucial role in vital biochemical activities, as components of enzymes and other molecular complexes. Excess iron promotes noxious free-radical reactions, so it has to be compartmentalized and maintained at fixed levels to avoid any toxic effects, largely based on its ability to catalyze the generation of radicals, which promote cell death and tissue injury. A balanced iron homeostasis is achieved by coordinated interaction among highly regulated uptake, storage, and secretion processes. Since there are no means to control iron excretion, excess iron accumulates in parenchymal organs and threatens cell survival. When iron overload, caused either by genetic or acquired factors, is present, fibrosis and cirrhosis are common findings, being the liver the main storage site for iron. Hepatic fibrosis is a dynamic process, from chronic liver damage to end-stage liver cirrhosis. Iron-induced oxidative stress is involved in this process as the primary cause of parenchymal cell necrosis or as activator of effectors cells (hepatic stellate cells, fibroblasts, Kupffer cells) or key mediators of hepatic fibrogenesis. Apart from being directly cytotoxic, iron and free radicals trigger increased synthesis of collagen in myofibroblast-like cells and activate granulocytes and Kupffer cells, resulting in increased formation of cytokines and further reactive oxygen species. Iron cytotoxicity and genotoxicity are moreover responsible for iron carcinogenic potentials.

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References

  1. Andriopoulos B Jr, Corradini E et al (2009) BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41(4):482–487

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Asare GA, Paterson AC, Kew MC et al (2006) Iron-free neoplastic nodules and hepatocellular carcinoma without cirrhosis in Wistar rats fed a diet high in iron. J Pathol 208:82–90

    Article  CAS  PubMed  Google Scholar 

  3. Barisani D, Pelucchi S, Mariani R et al (2008) Hepcidin and iron-related gene expression in subjects with dysmetabolic hepatic iron overload. J Hepatol 49:123–133

    Article  CAS  PubMed  Google Scholar 

  4. Ben-Arieh SV, Zimerman B, Smorodinsky NI et al (2001) Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J Virol 75:10557–10562

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Camaschella C (2005) Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 106(12):3710–3717

    Article  CAS  PubMed  Google Scholar 

  6. Corengia C, Galimberti S, Bovo G et al (2005) Iron accumulation in chronic hepatitis C: relation of hepatic iron distribution, HFE genotype, and disease course. Am J Clin Pathol 124:846–853

    Article  CAS  PubMed  Google Scholar 

  7. Dongiovanni P, Fracanzani AL et al (2010) Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. Am J Pathol 176:1006–1017

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Dongiovanni P, Fracanzani AL et al (2011) Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol 55(4):920–932

    Article  CAS  PubMed  Google Scholar 

  9. Facchini FS, Hua NW, Stoohs RA (2002) Effect of iron depletion in carbohydrate intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 122:931–939

    Article  CAS  PubMed  Google Scholar 

  10. Fargion S, Valenti L et al (2010) Hemochromatosis gene (HFE) mutations and cancer risk: expanding the clinical manifestations of hereditary iron overload. Hepatology 51(4):1119–1121

    Article  CAS  PubMed  Google Scholar 

  11. Fargion S, Valenti L, Fracanzani AL (2011) Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver disease. Dig Liver Dis 43:89–95

    Article  PubMed  Google Scholar 

  12. Feder JN, Gnirke A et al (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13(4):399–408

    Article  CAS  PubMed  Google Scholar 

  13. Finberg KE (2009) Iron-refractory iron deficiency anemia. Semin Hematol 46(4):378–386

    Article  CAS  PubMed  Google Scholar 

  14. Fracanzani AL, Conte D, Fraquelli M et al (2001) Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 33:647–651

    Article  CAS  PubMed  Google Scholar 

  15. Fracanzani AL, Fargion S et al (2005) Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma. Blood Cells Mol Dis 35:27–32

    Article  CAS  PubMed  Google Scholar 

  16. Halliwell B, Gutteridge JMC (1992) Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett 307:108–112

    Article  CAS  PubMed  Google Scholar 

  17. Harrison-Findik DD, Klein E, Crist C et al (2007) Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 46:1979–1985

    Article  CAS  PubMed  Google Scholar 

  18. Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–948

    Article  CAS  PubMed  Google Scholar 

  19. Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y, Makris C, Rothwarf D, Baud V, Natoli G, Guido F, Li N (2001) Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. Biofactors 15:87–89

    Article  CAS  PubMed  Google Scholar 

  20. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 46(7):678–684

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Lesbordes-Brion JC, Viatte L et al (2006) Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood 108(4):1402–1405

    Article  CAS  PubMed  Google Scholar 

  22. Létocart E, Le Gac G, Majore S et al (2009) A novel missense mutation in SLC40A1 results in resistance to hepcidin and confirms the existence of two ferroportin-associated iron overload diseases. Br J Haematol 147(3):379–385

    Article  PubMed  Google Scholar 

  23. Miura K, Taura K, Kodama Y et al (2008) Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 48:1420–1429

    Article  CAS  PubMed  Google Scholar 

  24. Moirand R, Mendler MH, Guillygomarc’h A et al (2000) Non-alcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload? J Hepatol 33:1024–1026

    Article  CAS  PubMed  Google Scholar 

  25. Muckenthaler MU (2008) Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab 8(1):1–3

    Article  CAS  PubMed  Google Scholar 

  26. Nahon P, Sutton A, Rufat P et al (2008) Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 134:102–110

    Article  CAS  PubMed  Google Scholar 

  27. Nahon P, Sutton A, Pessayre D et al (2011) Do genetic variations in antioxidant enzymes influence the course of hereditary hemochromatosis? Antioxid Redox Signal 15(1):31–38

    Article  CAS  PubMed  Google Scholar 

  28. Nemeth E, Tuttle MS et al (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704):2090–2093

    Article  CAS  PubMed  Google Scholar 

  29. Nishina S, Hino K, Korenaga M et al (2008) Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134:226–238

    Article  CAS  PubMed  Google Scholar 

  30. Pietrangelo A (2004) Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383–2397

    Article  CAS  PubMed  Google Scholar 

  31. Pietrangelo A (2007) Hemochromatosis: an endocrine liver disease. Hepatology 46(4):1291–1301

    Article  CAS  PubMed  Google Scholar 

  32. Pigeon C, Ilyin G et al (2001) 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

    Article  CAS  PubMed  Google Scholar 

  33. Piperno A, Mariani R et al (2000) Haemochromatosis in patients with beta-thalassaemia trait. Br J Haematol 111(3):908–914

    CAS  PubMed  Google Scholar 

  34. Ramsay AJ, Hooper JD et al (2009) Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematologica 94(6):840–849

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Ruddell RG, Hoang-Le D et al (2009) Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology 49(3):887–900

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Sartori M, Andorno S et al (2007) Heterozygous beta-globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis C. Gut 56(5):693–698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Smedsrod B, De Bleser PJ, Braet F, Lovisetti P, Vanderkerken K, Wisse E, Geerts A (1994) Cell biology of liver endothelial and Kupffer cells. Gut 35:1509–1516

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Sorretino P, D’Angelo S et al (2009) Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 50(2):351–357

    Article  Google Scholar 

  39. Sutton A, Nahon P, Pessayre D et al (2006) Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis. Cancer Res 66:2844–2852

    Article  CAS  PubMed  Google Scholar 

  40. Tung BY, Emond MJ, Bronner MP et al (2003) Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology 124:318–326

    Article  CAS  PubMed  Google Scholar 

  41. Valenti L, Conte D et al (2004) The mitochondrial superoxide dismutase A16V polymorphism in the cardiomyopathy associated with hereditary haemochromatosis. J Med Genet 41:946–950

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Valenti L, Pulixi EA, Arosio P et al (2007) Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis. Haematologica 92:1037–1042

    Article  CAS  PubMed  Google Scholar 

  43. Valenti L, Canavesi E et al (2010) Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 53(5):927–933

    Article  CAS  PubMed  Google Scholar 

  44. Valenti L, Fracanzani A, Bugianesi E et al (2010) HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 138:905–912

    Article  CAS  PubMed  Google Scholar 

  45. Valenti L, Rametta R et al (2012) The A736V TMPRSS6 polymorphism influences hepatic iron overload in nonalcoholic fatty liver disease. PLoS One 7(11):e48804

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Wood MJ, Powell LW et al (2008) Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 111(9):4456–4462

    Article  CAS  PubMed  Google Scholar 

  47. Zacharski LR, Chow BK et al (2008) Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 100(14):996–1002

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. IRCCS Ca’ Granda Foundation Policlinico Hospital Milan and Department of Pathophysiology and Transplantation, University of Milan, via F Sforza 35, Milan, 20122, Italy

    S. Pelusi, L. Valenti & Silvia Fargion

Authors
  1. S. Pelusi
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  2. L. Valenti
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  3. Silvia Fargion
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Correspondence to Silvia Fargion .

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Editors and Affiliations

  1. Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy

    Emanuele Albano

  2. Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, School of Medicine, University of Torino, Torino, Italy

    Maurizio Parola

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Pelusi, S., Valenti, L., Fargion, S. (2015). Oxidative Stress and Hepatic Iron Overload. In: Albano, E., Parola, M. (eds) Studies on Hepatic Disorders. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Cham. https://doi.org/10.1007/978-3-319-15539-5_15

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