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Review

Hepcidin and the iron enigma in HCV infection

, , , &
Pages 465-476 | Received 27 Nov 2013, Accepted 11 Mar 2014, Published online: 13 Mar 2014

References

  • Steinbicker AU, Muckenthaler MU. Out of balance--systemic iron homeostasis in iron-related disorders. Nutrients 2013; 5:3034 - 61; http://dx.doi.org/10.3390/nu5083034; PMID: 23917168
  • Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA, Ho LP, Townsend AR, Drakesmith H. Hepcidin regulation by innate immune and infectious stimuli. Blood 2011; 118:4129 - 39; http://dx.doi.org/10.1182/blood-2011-04-351957; PMID: 21873546
  • MacKenzie EL, Iwasaki K, Tsuji Y. Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal 2008; 10:997 - 1030; http://dx.doi.org/10.1089/ars.2007.1893; PMID: 18327971
  • Tomosugi N, Kawabata H, Wakatabe R, Higuchi M, Yamaya H, Umehara H, Ishikawa I. Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood 2006; 108:1381 - 7; http://dx.doi.org/10.1182/blood-2005-10-4043; PMID: 16621968
  • Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis 2008; 40:132 - 8; http://dx.doi.org/10.1016/j.bcmd.2007.07.009; PMID: 17905609
  • Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276:7806 - 10; http://dx.doi.org/10.1074/jbc.M008922200; PMID: 11113131
  • 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 2003; 101:2461 - 3; http://dx.doi.org/10.1182/blood-2002-10-3235; PMID: 12433676
  • Ganz T. Hepcidin--a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol 2005; 18:171 - 82; http://dx.doi.org/10.1016/j.beha.2004.08.020; PMID: 15737883
  • 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 2004; 306:2090 - 3; http://dx.doi.org/10.1126/science.1104742; PMID: 15514116
  • 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 2002; 110:1037 - 44; http://dx.doi.org/10.1172/JCI0215686; PMID: 12370282
  • Thomas DL. Global control of hepatitis C: where challenge meets opportunity. Nat Med 2013; 19:850 - 8; http://dx.doi.org/10.1038/nm.3184; PMID: 23836235
  • Hoffman B, Liu Q. Hepatitis C viral protein translation: mechanisms and implications in developing antivirals. Liver Int 2011; 31:1449 - 67; http://dx.doi.org/10.1111/j.1478-3231.2011.02543.x; PMID: 21745290
  • Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013; 19:837 - 49; http://dx.doi.org/10.1038/nm.3248; PMID: 23836234
  • Valenti L, Pulixi EA, Arosio P, Cremonesi L, Biasiotto G, Dongiovanni P, Maggioni M, Fargion S, Fracanzani AL. Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis. Haematologica 2007; 92:1037 - 42; http://dx.doi.org/10.3324/haematol.11281; PMID: 17640859
  • Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol 2007; 69:69 - 85; http://dx.doi.org/10.1146/annurev.physiol.69.031905.164337; PMID: 17014365
  • Kohgo Y, Ikuta K, Ohtake T, Torimoto Y, Kato J. Body iron metabolism and pathophysiology of iron overload. Int J Hematol 2008; 88:7 - 15; http://dx.doi.org/10.1007/s12185-008-0120-5; PMID: 18594779
  • Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000; 275:19906 - 12; http://dx.doi.org/10.1074/jbc.M000713200; PMID: 10747949
  • Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000; 403:776 - 81; http://dx.doi.org/10.1038/35001596; PMID: 10693807
  • McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000; 5:299 - 309; http://dx.doi.org/10.1016/S1097-2765(00)80425-6; PMID: 10882071
  • Marro S, Chiabrando D, Messana E, Stolte J, Turco E, Tolosano E, Muckenthaler MU. Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter. Haematologica 2010; 95:1261 - 8; http://dx.doi.org/10.3324/haematol.2009.020123; PMID: 20179090
  • Brasse-Lagnel C, Karim Z, Letteron P, Bekri S, Bado A, Beaumont C. Intestinal DMT1 cotransporter is down-regulated by hepcidin via proteasome internalization and degradation. Gastroenterology 2011; 140:1261 - 71, e1; http://dx.doi.org/10.1053/j.gastro.2010.12.037; PMID: 21199652
  • Franchini M, Montagnana M, Lippi G. Hepcidin and iron metabolism: from laboratory to clinical implications. Clin Chim Acta 2010; 411:1565 - 9; http://dx.doi.org/10.1016/j.cca.2010.07.003; PMID: 20620132
  • 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 2009; 9:217 - 27; http://dx.doi.org/10.1016/j.cmet.2009.01.010; PMID: 19254567
  • Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2005; 2:399 - 409; http://dx.doi.org/10.1016/j.cmet.2005.10.010; PMID: 16330325
  • Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425 - 33; http://dx.doi.org/10.1182/blood-2011-01-258467; PMID: 21346250
  • Castoldi M, Muckenthaler MU. Regulation of iron homeostasis by microRNAs. Cell Mol Life Sci 2012; 2012:9; PMID: 22678662
  • Zumbrennen-Bullough KWQ, Chen W, Babitt J. MicroRNA-130a Downregulates Hepcidin Expression during Iron Deficiency by Targeting ALK2. Proceedings of Fifth Congress of the International BioIron Society (IBIS), Biennial World Meeting (BioIron 2013); London, UK 14–18 April 2013 2013.
  • Zhang X, Rovin BH. Beyond anemia: hepcidin, monocytes and inflammation. Biol Chem 2013; 394:231 - 8; http://dx.doi.org/10.1515/bchm-2012-0217; PMID: 23314535
  • Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002; 99:3505 - 16; http://dx.doi.org/10.1182/blood.V99.10.3505; PMID: 11986201
  • Cairo G, Recalcati S. Iron-regulatory proteins: molecular biology and pathophysiological implications. Expert Rev Mol Med 2007; 9:1 - 13; http://dx.doi.org/10.1017/S1462399407000531; PMID: 18053288
  • Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J 2011; 434:365 - 81; http://dx.doi.org/10.1042/BJ20101825; PMID: 21348856
  • Muckenthaler MU. Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab 2008; 8:1 - 3; http://dx.doi.org/10.1016/j.cmet.2008.06.009; PMID: 18590684
  • Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis 1996; 16:13 - 30; http://dx.doi.org/10.1055/s-2007-1007215; PMID: 8723320
  • Videla LA, Fernández V, Tapia G, Varela P. Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells. Biometals 2003; 16:103 - 11; http://dx.doi.org/10.1023/A:1020707811707; PMID: 12572670
  • Braliou GG, Verga Falzacappa MV, Chachami G, Casanovas G, Muckenthaler MU, Simos G. 2-Oxoglutarate-dependent oxygenases control hepcidin gene expression. J Hepatol 2008; 48:801 - 10; http://dx.doi.org/10.1016/j.jhep.2007.12.021; PMID: 18313788
  • 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 2011; 300:C888 - 95; http://dx.doi.org/10.1152/ajpcell.00121.2010; PMID: 21289291
  • Deugnier Y, Turlin B. Pathology of hepatic iron overload. World J Gastroenterol 2007; 13:4755 - 60; PMID: 17729397
  • Ko C, Siddaiah N, Berger J, Gish R, Brandhagen D, Sterling RK, Cotler SJ, Fontana RJ, McCashland TM, Han SH, et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007; 27:1394 - 401; http://dx.doi.org/10.1111/j.1478-3231.2007.01596.x; PMID: 17927713
  • Fujita N, Sugimoto R, Takeo M, Urawa N, Mifuji R, Tanaka H, Kobayashi Y, Iwasa M, Watanabe S, Adachi Y, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007; 13:97 - 104; http://dx.doi.org/10.2119/2006-00057.Fujita; PMID: 17515961
  • Sikorska K, Stalke P, Izycka-Swieszewska E, Romanowski T, Bielawski KP. The role of iron overload and HFE gene mutations in the era of pegylated interferon and ribavirin treatment of chronic hepatitis C. Med Sci Monit 2010; 16:CR137 - 43; PMID: 20190684
  • Drakesmith H, Prentice A. Viral infection and iron metabolism. Nat Rev Microbiol 2008; 6:541 - 52; http://dx.doi.org/10.1038/nrmicro1930; PMID: 18552864
  • Maliken BD, Nelson JE, Kowdley KV. The hepcidin circuits act: balancing iron and inflammation. Hepatology 2011; 53:1764 - 6; http://dx.doi.org/10.1002/hep.24267; PMID: 21520181
  • De Domenico I, Ward DM, Kaplan J. Hepcidin regulation: ironing out the details. J Clin Invest 2007; 117:1755 - 8; http://dx.doi.org/10.1172/JCI32701; PMID: 17607352
  • Poli M, Luscieti S, Gandini V, Maccarinelli F, Finazzi D, Silvestri L, Roetto A, Arosio P. Transferrin receptor 2 and HFE regulate furin expression via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) signaling. Implications for transferrin-dependent hepcidin regulation. Haematologica 2010; 95:1832 - 40; http://dx.doi.org/10.3324/haematol.2010.027003; PMID: 20634490
  • Fontana RJ, Israel J, LeClair P, Banner BF, Tortorelli K, Grace N, Levine RA, Fiarman G, Thiim M, Tavill AS, et al. Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 2000; 31:730 - 6; http://dx.doi.org/10.1002/hep.510310325; PMID: 10706565
  • Bonkovsky HL, Naishadham D, Lambrecht RW, Chung RT, Hoefs JC, Nash SR, Rogers TE, Banner BF, Sterling RK, Donovan JA, et al, HALT-C Trial Group. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 2006; 131:1440 - 51; http://dx.doi.org/10.1053/j.gastro.2006.08.036; PMID: 17101320
  • Meynard D, Babitt JL, Lin HY. The liver: conductor of systemic iron balance. Blood 2014; 123:168 - 76; http://dx.doi.org/10.1182/blood-2013-06-427757; PMID: 24200681
  • Di Bisceglie AM, Simpson LH, Lotze MT, Hoofnagle JH. Development of hepatocellular carcinoma among patients with chronic liver disease due to hepatitis C viral infection. J Clin Gastroenterol 1994; 19:222 - 6; http://dx.doi.org/10.1097/00004836-199410000-00011; PMID: 7528758
  • Ivanov AV, Bartosch B, Smirnova OA, Isaguliants MG, Kochetkov SN. HCV and oxidative stress in the liver. Viruses 2013; 5:439 - 69; http://dx.doi.org/10.3390/v5020439; PMID: 23358390
  • Buratti E, Tisminetzky S, Zotti M, Baralle FE. Functional analysis of the interaction between HCV 5’UTR and putative subunits of eukaryotic translation initiation factor eIF3. Nucleic Acids Res 1998; 26:3179 - 87; http://dx.doi.org/10.1093/nar/26.13.3179; PMID: 9628916
  • Cho H, Lee HC, Jang SK, Kim YK. Iron increases translation initiation directed by internal ribosome entry site of hepatitis C virus. Virus Genes 2008; 37:154 - 60; http://dx.doi.org/10.1007/s11262-008-0250-0; PMID: 18566883
  • Kieft JS, Zhou K, Jubin R, Doudna JA. Mechanism of ribosome recruitment by hepatitis C IRES RNA. RNA 2001; 7:194 - 206; http://dx.doi.org/10.1017/S1355838201001790; PMID: 11233977
  • Theurl I, Zoller H, Obrist P, Datz C, Bachmann F, Elliott RM, Weiss G. Iron regulates hepatitis C virus translation via stimulation of expression of translation initiation factor 3. J Infect Dis 2004; 190:819 - 25; http://dx.doi.org/10.1086/422261; PMID: 15272411
  • Johnson KR, Merrick WC, Zoll WL, Zhu Y. Identification of cDNA clones for the large subunit of eukaryotic translation initiation factor 3. Comparison of homologues from human, Nicotiana tabacum, Caenorhabditis elegans, and Saccharomyces cerevisiae. J Biol Chem 1997; 272:7106 - 13; http://dx.doi.org/10.1074/jbc.272.11.7106; PMID: 9054404
  • Izumi N, Enomoto N, Uchihara M, Murakami T, Ono K, Noguchi O, Miyake S, Nouchi T, Fujisawa K, Marumo F, et al. Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus. Dig Dis Sci 1996; 41:989 - 94; http://dx.doi.org/10.1007/BF02091542; PMID: 8625774
  • Liu Y, An D, Sun R, Jin L, Wang Q. Inhibition of translation initiation factors might be the potential therapeutic targets for HCV patients with hepatic iron overload. Med Hypotheses 2012; 78:142 - 3; http://dx.doi.org/10.1016/j.mehy.2011.10.011; PMID: 22047986
  • Bartolomei G, Cevik RE, Marcello A. Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes. J Gen Virol 2011; 92:2072 - 81; http://dx.doi.org/10.1099/vir.0.032706-0; PMID: 21593278
  • Fillebeen C, Pantopoulos K. Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells. J Hepatol 2010; 53:995 - 9; http://dx.doi.org/10.1016/j.jhep.2010.04.044; PMID: 20813419
  • Fillebeen C, Rivas-Estilla AM, Bisaillon M, Ponka P, Muckenthaler M, Hentze MW, Koromilas AE, Pantopoulos K. Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C Virus. J Biol Chem 2005; 280:9049 - 57; http://dx.doi.org/10.1074/jbc.M412687200; PMID: 15637067
  • Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection. Gastroenterology 2003; 124:1509 - 23; http://dx.doi.org/10.1016/S0016-5085(03)00275-0; PMID: 12730889
  • Tung BY, Emond MJ, Bronner MP, Raaka SD, Cotler SJ, Kowdley KV. Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology 2003; 124:318 - 26; http://dx.doi.org/10.1053/gast.2003.50046; PMID: 12557137
  • Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidaka I, et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 2008; 134:226 - 38; http://dx.doi.org/10.1053/j.gastro.2007.10.011; PMID: 18166355
  • Moriya K, Miyoshi H, Shinzawa S, Tsutsumi T, Fujie H, Goto K, Shintani Y, Yotsuyanagi H, Koike K. Hepatitis C virus core protein compromises iron-induced activation of antioxidants in mice and HepG2 cells. J Med Virol 2010; 82:776 - 92; http://dx.doi.org/10.1002/jmv.21661; PMID: 20336713
  • 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 2007; 356:312 - 7; http://dx.doi.org/10.1016/j.bbrc.2007.02.137; PMID: 17349976
  • Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008; 48:1420 - 9; http://dx.doi.org/10.1002/hep.22486; PMID: 18671304
  • Nagashima M, Kudo M, Chung H, Ishikawa E, Hagiwara S, Nakatani T, Dote K. Regulatory failure of serum prohepcidin levels in patients with hepatitis C. Hepatol Res 2006; 36:288 - 93; http://dx.doi.org/10.1016/j.hepres.2006.08.006; PMID: 16979376
  • Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007; 109:353 - 8; http://dx.doi.org/10.1182/blood-2006-07-033969; PMID: 16946298
  • Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood 2006; 108:3204 - 9; http://dx.doi.org/10.1182/blood-2006-06-027631; PMID: 16835372
  • Miyachi H, Kobayashi Y, Relja B, Fujita N, Iwasa M, Gabazza EC, Takei Y. Effect of suppressor of cytokine signaling on hepcidin production in hepatitis C virus replicon cells. Hepatol Res 2011; 41:364 - 74; http://dx.doi.org/10.1111/j.1872-034X.2011.00777.x; PMID: 21348906
  • Fillebeen C, Muckenthaler M, Andriopoulos B, Bisaillon M, Mounir Z, Hentze MW, Koromilas AE, Pantopoulos K. Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J Hepatol 2007; 47:12 - 22; http://dx.doi.org/10.1016/j.jhep.2007.01.035; PMID: 17399844
  • Kanda T, Yokosuka O, Omata M, Hepatitis C. Virus and Hepatocellular Carcinoma. Biology 2013; 2:304 - 16; http://dx.doi.org/10.3390/biology2010304
  • Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 2005; 41:1096 - 105; http://dx.doi.org/10.1002/hep.20668; PMID: 15841445
  • Kochlios E, Foka P, Tsitoura E, Doumba P, Koskinas J, Mavromara P. Effect of HCV core and core+1/S on pro- and anti-inflammatory cytokine and chemokine gene expression. Bologna, Italy: Medimond SRL Publ., 2010.
  • Tacke RS, Tosello-Trampont A, Nguyen V, Mullins DW, Hahn YS. Extracellular hepatitis C virus core protein activates STAT3 in human monocytes/macrophages/dendritic cells via an IL-6 autocrine pathway. J Biol Chem 2011; 286:10847 - 55; http://dx.doi.org/10.1074/jbc.M110.217653; PMID: 21282107
  • Yoshida T, Hanada T, Tokuhisa T, Kosai K, Sata M, Kohara M, Yoshimura A. Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation. J Exp Med 2002; 196:641 - 53; http://dx.doi.org/10.1084/jem.20012127; PMID: 12208879
  • Cozza G, Mazzorana M, Papinutto E, Bain J, Elliott M, di Maira G, Gianoncelli A, Pagano MA, Sarno S, Ruzzene M, et al. Quinalizarin as a potent, selective and cell-permeable inhibitor of protein kinase CK2. Biochem J 2009; 421:387 - 95; http://dx.doi.org/10.1042/BJ20090069; PMID: 19432557
  • Lin W, Choe WH, Hiasa Y, Kamegaya Y, Blackard JT, Schmidt EV, Chung RT. Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology 2005; 128:1034 - 41; http://dx.doi.org/10.1053/j.gastro.2005.02.006; PMID: 15825084
  • Taniguchi H, Kato N, Otsuka M, Goto T, Yoshida H, Shiratori Y, Omata M. Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. J Med Virol 2004; 72:52 - 9; http://dx.doi.org/10.1002/jmv.10545; PMID: 14635011
  • Pavio N, Battaglia S, Boucreux D, Arnulf B, Sobesky R, Hermine O, Brechot C. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway. Oncogene 2005; 24:6119 - 32; http://dx.doi.org/10.1038/sj.onc.1208749; PMID: 16007207
  • Battaglia S, Benzoubir N, Nobilet S, Charneau P, Samuel D, Zignego AL, Atfi A, Bréchot C, Bourgeade MF. Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition. PLoS One 2009; 4:e4355; http://dx.doi.org/10.1371/journal.pone.0004355; PMID: 19190755
  • Tsutsumi T, Suzuki T, Moriya K, Shintani Y, Fujie H, Miyoshi H, Matsuura Y, Koike K, Miyamura T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology 2003; 38:820 - 8; http://dx.doi.org/10.1002/hep.1840380408; PMID: 14512869
  • Serti E, Doumba PP, Thyphronitis G, Tsitoura P, Katsarou K, Foka P, Konstandoulakis MM, Koskinas J, Mavromara P, Georgopoulou U. Modulation of IL-2 expression after uptake of hepatitis C virus non-enveloped capsid-like particles: the role of p38 kinase. Cell Mol Life Sci 2011; 68:505 - 22; http://dx.doi.org/10.1007/s00018-010-0466-8; PMID: 20680391
  • Hayashi J, Aoki H, Kajino K, Moriyama M, Arakawa Y, Hino O. Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha. Hepatology 2000; 32:958 - 61; http://dx.doi.org/10.1053/jhep.2000.19343; PMID: 11050045
  • Aoyagi K, Ohue C, Iida K, Kimura T, Tanaka E, Kiyosawa K, Yagi S. Development of a simple and highly sensitive enzyme immunoassay for hepatitis C virus core antigen. J Clin Microbiol 1999; 37:1802 - 8; PMID: 10325327
  • Katsarou K, Lavdas AA, Tsitoura P, Serti E, Markoulatos P, Mavromara P, Georgopoulou U. Endocytosis of hepatitis C virus non-enveloped capsid-like particles induces MAPK-ERK1/2 signaling events. Cell Mol Life Sci 2010; 67:2491 - 506; http://dx.doi.org/10.1007/s00018-010-0351-5; PMID: 20358251
  • Zhao LJ, Wang L, Ren H, Cao J, Li L, Ke JS, Qi ZT. Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors. Exp Cell Res 2005; 305:23 - 32; http://dx.doi.org/10.1016/j.yexcr.2004.12.024; PMID: 15777784
  • Zhao LJ, Zhao P, Chen QL, Ren H, Pan W, Qi ZT. Mitogen-activated protein kinase signalling pathways triggered by the hepatitis C virus envelope protein E2: implications for the prevention of infection. Cell Prolif 2007; 40:508 - 21; http://dx.doi.org/10.1111/j.1365-2184.2007.00453.x; PMID: 17635518
  • Hassan M, Ghozlan H, Abdel-Kader O. Activation of c-Jun NH2-terminal kinase (JNK) signaling pathway is essential for the stimulation of hepatitis C virus (HCV) non-structural protein 3 (NS3)-mediated cell growth. Virology 2005; 333:324 - 36; http://dx.doi.org/10.1016/j.virol.2005.01.008; PMID: 15721365
  • Feng DY, Sun Y, Cheng RX, Ouyang XM, Zheng H. Effect of hepatitis C virus nonstructural protein NS3 on proliferation and MAPK phosphorylation of normal hepatocyte line. World J Gastroenterol 2005; 11:2157 - 61; PMID: 15810084
  • Pei R, Chen H, Lu L, Zhu W, Beckebaum S, Cicinnati V, Lu M, Chen X. Hepatitis C virus infection induces the expression of amphiregulin, a factor related to the activation of cellular survival pathways and required for efficient viral assembly. J Gen Virol 2011; 92:2237 - 48; http://dx.doi.org/10.1099/vir.0.032581-0; PMID: 21653755
  • Verga-Gérard A, Porcherot M, Meyniel-Schicklin L, André P, Lotteau V, Perrin-Cocon L. Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF-β signaling. FASEB J 2013; 27:4027 - 40; http://dx.doi.org/10.1096/fj.13-229187; PMID: 23781096
  • Weizer-Stern O, Adamsky K, Margalit O, Ashur-Fabian O, Givol D, Amariglio N, Rechavi G. Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. Br J Haematol 2007; 138:253 - 62; http://dx.doi.org/10.1111/j.1365-2141.2007.06638.x; PMID: 17593032
  • Sarcar B, Ghosh AK, Steele R, Ray R, Ray RB. Hepatitis C virus NS5A mediated STAT3 activation requires co-operation of Jak1 kinase. Virology 2004; 322:51 - 60; http://dx.doi.org/10.1016/j.virol.2004.01.008; PMID: 15063116
  • Presser LD, Haskett A, Waris G. Hepatitis C virus-induced furin and thrombospondin-1 activate TGF-β1: role of TGF-β1 in HCV replication. Virology 2011; 412:284 - 96; http://dx.doi.org/10.1016/j.virol.2010.12.051; PMID: 21296375
  • Choi SH, Hwang SB. Modulation of the transforming growth factor-beta signal transduction pathway by hepatitis C virus nonstructural 5A protein. J Biol Chem 2006; 281:7468 - 78; http://dx.doi.org/10.1074/jbc.M512438200; PMID: 16407286
  • Macdonald A, Crowder K, Street A, McCormick C, Saksela K, Harris M. The hepatitis C virus non-structural NS5A protein inhibits activating protein-1 function by perturbing ras-ERK pathway signaling. J Biol Chem 2003; 278:17775 - 84; http://dx.doi.org/10.1074/jbc.M210900200; PMID: 12621033
  • Georgopoulou U, Caravokiri K, Mavromara P. Suppression of the ERK1/2 signaling pathway from HCV NS5A protein expressed by herpes simplex recombinant viruses. Arch Virol 2003; 148:237 - 51; http://dx.doi.org/10.1007/s00705-002-0925-0; PMID: 12556990
  • Nelson JE, Klintworth H, Kowdley KV. Iron metabolism in Nonalcoholic Fatty Liver Disease. Curr Gastroenterol Rep 2012; 14:8 - 16; http://dx.doi.org/10.1007/s11894-011-0234-4; PMID: 22124850
  • Aso Y, Wakabayashi S, Yamamoto R, Matsutomo R, Takebayashi K, Inukai T. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care 2005; 28:2211 - 6; http://dx.doi.org/10.2337/diacare.28.9.2211; PMID: 16123492
  • Younossi ZM, McCullough AJ. Metabolic syndrome, non-alcoholic fatty liver disease and hepatitis C virus: impact on disease progression and treatment response. Liver Int 2009; 29:Suppl 2 3 - 12; http://dx.doi.org/10.1111/j.1478-3231.2008.01949.x; PMID: 19187068
  • Miyanari Y, Atsuzawa K, Usuda N, Watashi K, Hishiki T, Zayas M, Bartenschlager R, Wakita T, Hijikata M, Shimotohno K. The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 2007; 9:1089 - 97; http://dx.doi.org/10.1038/ncb1631; PMID: 17721513
  • Moriishi K, Mochizuki R, Moriya K, Miyamoto H, Mori Y, Abe T, Murata S, Tanaka K, Miyamura T, Suzuki T, et al. Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci U S A 2007; 104:1661 - 6; http://dx.doi.org/10.1073/pnas.0607312104; PMID: 17234812
  • Björnsson E, Angulo P. Hepatitis C and steatosis. Arch Med Res 2007; 38:621 - 7; http://dx.doi.org/10.1016/j.arcmed.2006.09.001; PMID: 17613353
  • Roe B, Kensicki E, Mohney R, Hall WW. Metabolomic profile of hepatitis C virus-infected hepatocytes. PLoS One 2011; 6:e23641; http://dx.doi.org/10.1371/journal.pone.0023641; PMID: 21853158
  • Roingeard P, Hourioux C. Hepatitis C virus core protein, lipid droplets and steatosis. J Viral Hepat 2008; 15:157 - 64; http://dx.doi.org/10.1111/j.1365-2893.2007.00953.x; PMID: 18086178
  • Koike K, Moriya K, Matsuura Y. Animal models for hepatitis C and related liver disease. Hepatol Res 2010; 40:69 - 82; http://dx.doi.org/10.1111/j.1872-034X.2009.00593.x; PMID: 20156300
  • Sato Y, Kato J, Takimoto R, Takada K, Kawano Y, Miyanishi K, Kobune M, Sato Y, Takayama T, Matunaga T, et al. Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor alpha expression via activation of nuclear factor-kappaB. Gut 2006; 55:1801 - 8; http://dx.doi.org/10.1136/gut.2005.070417; PMID: 16581947
  • Gómez-Gonzalo M, Benedicto I, Carretero M, Lara-Pezzi E, Maldonado-Rodríguez A, Moreno-Otero R, Lai MM, López-Cabrera M. Hepatitis C virus core protein regulates p300/CBP co-activation function. Possible role in the regulation of NF-AT1 transcriptional activity. Virology 2004; 328:120 - 30; http://dx.doi.org/10.1016/j.virol.2004.06.044; PMID: 15380363
  • Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T. Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology 2002; 35:937 - 46; http://dx.doi.org/10.1053/jhep.2002.32470; PMID: 11915042
  • Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol 2007; 81:8122 - 30; http://dx.doi.org/10.1128/JVI.00125-07; PMID: 17507484
  • García-Mediavilla MV, Pisonero-Vaquero S, Lima-Cabello E, Benedicto I, Majano PL, Jorquera F, González-Gallego J, Sánchez-Campos S. Liver X receptor α-mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication. Lab Invest 2012; 92:1191 - 202; http://dx.doi.org/10.1038/labinvest.2012.88; PMID: 22641099
  • Dharancy S, Malapel M, Perlemuter G, Roskams T, Cheng Y, Dubuquoy L, Podevin P, Conti F, Canva V, Philippe D, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology 2005; 128:334 - 42; http://dx.doi.org/10.1053/j.gastro.2004.11.016; PMID: 15685545
  • Kim K, Kim KH, Ha E, Park JY, Sakamoto N, Cheong J. Hepatitis C virus NS5A protein increases hepatic lipid accumulation via induction of activation and expression of PPARgamma. FEBS Lett 2009; 583:2720 - 6; http://dx.doi.org/10.1016/j.febslet.2009.07.034; PMID: 19631645
  • Kim KH, Hong SP, Kim K, Park MJ, Kim KJ, Cheong J. HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. Biochem Biophys Res Commun 2007; 355:883 - 8; http://dx.doi.org/10.1016/j.bbrc.2007.02.044; PMID: 17331464
  • Foka P, Karamichali E, Dalagiorgou G, Serti E, Doumba PP, Pissas G, Kakkanas A, Kazazi D, Kochlios E, Gaitanou M, et al. Hepatitis C virus modulates lipid regulatory factor Angiopoietin-like 3 gene expression by repressing HNF-1alpha activity. J Hepatol 2014; 60:30 - 8; http://dx.doi.org/10.1016/j.jhep.2013.08.016; PMID: 23978712
  • Dongiovanni P, Fracanzani AL, Fargion S, Valenti L. Iron in fatty liver and in the metabolic syndrome: a promising therapeutic target. J Hepatol 2011; 55:920 - 32; http://dx.doi.org/10.1016/j.jhep.2011.05.008; PMID: 21718726
  • Wlazlo N, Greevenbroek MM. Lipid metabolism: a role for iron?. Curr Opin Lipidol 2012; 23:258 - 9; http://dx.doi.org/10.1097/MOL.0b013e328354752d; PMID: 22576585
  • Haap M, Machann J, von Friedeburg C, Schick F, Stefan N, Schwenzer NF, Fritsche A, Häring HU, Thamer C. Insulin sensitivity and liver fat: role of iron load. J Clin Endocrinol Metab 2011; 96:E958 - 61; http://dx.doi.org/10.1210/jc.2010-2682; PMID: 21430023
  • Ahmed U, Latham PS, Oates PS. Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis. World J Gastroenterol 2012; 18:4651 - 8; http://dx.doi.org/10.3748/wjg.v18.i34.4651; PMID: 23002334
  • Choi JS, Koh IU, Lee HJ, Kim WH, Song J. Effects of excess dietary iron and fat on glucose and lipid metabolism. J Nutr Biochem 2013; 24:1634 - 44; http://dx.doi.org/10.1016/j.jnutbio.2013.02.004; PMID: 23643521
  • Lewis M, Iammarino RM. Lipemia in rodent iron-deficiency anemia. J Lab Clin Med 1971; 78:546 - 54; PMID: 5114051
  • Sherman AR. Lipogenesis in iron-deficient adult rats. Lipids 1978; 13:473 - 8; http://dx.doi.org/10.1007/BF02533616; PMID: 692295
  • Tosco A, Fontanella B, Danise R, Cicatiello L, Grober OM, Ravo M, Weisz A, Marzullo L. Molecular bases of copper and iron deficiency-associated dyslipidemia: a microarray analysis of the rat intestinal transcriptome. Genes Nutr 2010; 5:1 - 8; http://dx.doi.org/10.1007/s12263-009-0153-2; PMID: 19821111
  • Stangl GI, Kirchgessner M. Different degrees of moderate iron deficiency modulate lipid metabolism of rats. Lipids 1998; 33:889 - 95; http://dx.doi.org/10.1007/s11745-998-0285-8; PMID: 9778136
  • Rao GA, Crane RT, Larkin EC. Reduced plasma lecithin cholesterol acyl transferase activity in rats fed iron-deficient diets. Lipids 1983; 18:673 - 6; http://dx.doi.org/10.1007/BF02534575; PMID: 6656532
  • Bacon BR, Britton RS, O’Neill R. Effects of vitamin E deficiency on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. Hepatology 1989; 9:398 - 404; http://dx.doi.org/10.1002/hep.1840090309; PMID: 2920996
  • Feldman ES, Bacon BR. Hepatic mitochondrial oxidative metabolism and lipid peroxidation in experimental hexachlorobenzene-induced porphyria with dietary carbonyl iron overload. Hepatology 1989; 9:686 - 92; http://dx.doi.org/10.1002/hep.1840090505; PMID: 2707735
  • Ramm GA, Crawford DH, Powell LW, Walker NI, Fletcher LM, Halliday JW. Hepatic stellate cell activation in genetic haemochromatosis. Lobular distribution, effect of increasing hepatic iron and response to phlebotomy. J Hepatol 1997; 26:584 - 92; http://dx.doi.org/10.1016/S0168-8278(97)80424-2; PMID: 9075666
  • Bories G, Colin S, Vanhoutte J, Derudas B, Copin C, Fanchon M, Daoudi M, Belloy L, Haulon S, Zawadzki C, et al. Liver X receptor activation stimulates iron export in human alternative macrophages. Circ Res 2013; 113:1196 - 205; http://dx.doi.org/10.1161/CIRCRESAHA.113.301656; PMID: 24036496
  • Bonomo LdeF, Silva M, Oliveira RdeP, Silva ME, Pedrosa ML. Iron overload potentiates diet-induced hypercholesterolemia and reduces liver PPAR-α expression in hamsters. J Biochem Mol Toxicol 2012; 26:224 - 9; http://dx.doi.org/10.1002/jbt.21410; PMID: 22570273
  • Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 1995; 22:449 - 56; http://dx.doi.org/10.1016/0168-8278(95)80108-1; PMID: 7545199
  • Kageyama F, Kobayashi Y, Kawasaki T, Toyokuni S, Uchida K, Nakamura H. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C. Am J Gastroenterol 2000; 95:1041 - 50; http://dx.doi.org/10.1111/j.1572-0241.2000.01979.x; PMID: 10763957
  • Konishi M, Iwasa M, Araki J, Kobayashi Y, Katsuki A, Sumida Y, Nakagawa N, Kojima Y, Watanabe S, Adachi Y, et al. Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane. J Gastroenterol Hepatol 2006; 21:1821 - 5; http://dx.doi.org/10.1111/j.1440-1746.2006.04420.x; PMID: 17074020
  • Barisani D, Pelucchi S, Mariani R, Galimberti S, Trombini P, Fumagalli D, Meneveri R, Nemeth E, Ganz T, Piperno A. Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload. J Hepatol 2008; 49:123 - 33; http://dx.doi.org/10.1016/j.jhep.2008.03.011; PMID: 18462824
  • Hézode C, Cazeneuve C, Coué O, Roudot-Thoraval F, Lonjon I, Bastie A, Duvoux C, Pawlotsky JM, Zafrani ES, Amselem S, et al. Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions. J Hepatol 1999; 31:979 - 84; http://dx.doi.org/10.1016/S0168-8278(99)80308-0; PMID: 10604569
  • Lok AS, Everhart JE, Chung RT, Kim HY, Everson GT, Hoefs JC, Greenson JK, Sterling RK, Lindsay KL, Lee WM, et al, HALT-C Trial Group. Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology 2009; 49:1828 - 37; http://dx.doi.org/10.1002/hep.22865; PMID: 19291787
  • Macaluso FS, Maida M, Minissale MG, Li Vigni T, Attardo S, Orlando E, Petta S. Metabolic factors and chronic hepatitis C: a complex interplay. Biomed Res Int 2013; 2013:564645; http://dx.doi.org/10.1155/2013/564645; PMID: 23956991
  • Hino K, Nishina S, Hara Y. Iron metabolic disorder in chronic hepatitis C: mechanisms and relevance to hepatocarcinogenesis. J Gastroenterol Hepatol 2013; 28:Suppl 4 93 - 8; http://dx.doi.org/10.1111/jgh.12243; PMID: 24251712
  • Adinolfi LE, Durante-Mangoni E, Zampino R, Ruggiero G. Review article: hepatitis C virus-associated steatosis--pathogenic mechanisms and clinical implications. Aliment Pharmacol Ther 2005; 22:Suppl 2 52 - 5; http://dx.doi.org/10.1111/j.1365-2036.2005.02597.x; PMID: 16225474
  • Mueller S, Afdhal NH, Schuppan D. Iron, HCV, and liver cancer: hard metal setting the pace?. Gastroenterology 2006; 130:2229 - 34; http://dx.doi.org/10.1053/j.gastro.2006.05.006; PMID: 16762645
  • Ward DG, Roberts K, Brookes MJ, Joy H, Martin A, Ismail T, Spychal R, Iqbal T, Tselepis C. Increased hepcidin expression in colorectal carcinogenesis. World J Gastroenterol 2008; 14:1339 - 45; http://dx.doi.org/10.3748/wjg.14.1339; PMID: 18322945
  • Piperno A, Mariani R, Trombini P, Girelli D. Hepcidin modulation in human diseases: from research to clinic. World J Gastroenterol 2009; 15:538 - 51; http://dx.doi.org/10.3748/wjg.15.538; PMID: 19195055
  • Tsochatzis E, Papatheodoridis GV, Koliaraki V, Hadziyannis E, Kafiri G, Manesis EK, Mamalaki A, Archimandritis AJ. Serum hepcidin levels are related to the severity of liver histological lesions in chronic hepatitis C. J Viral Hepat 2010; 17:800 - 6; http://dx.doi.org/10.1111/j.1365-2893.2009.01244.x; PMID: 20002304
  • Mitsuyoshi H, Yasui K, Yamaguchi K, Minami M, Okanoue T, Itoh Y. Pathogenic Role of Iron Deposition in Reticuloendothelial Cells during the Development of Chronic Hepatitis C. Int J Hepatol 2013; 2013:686420; http://dx.doi.org/10.1155/2013/686420; PMID: 23653861
  • Pietrangelo A, Montosi G, Garuti C, Contri M, Giovannini F, Ceccarelli D, Masini A. Iron-induced oxidant stress in nonparenchymal liver cells: mitochondrial derangement and fibrosis in acutely iron-dosed gerbils and its prevention by silybin. J Bioenerg Biomembr 2002; 34:67 - 79; http://dx.doi.org/10.1023/A:1013874804911; PMID: 11860182
  • Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, Unalp-Arida A, Kowdley KV, Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53:448 - 57; http://dx.doi.org/10.1002/hep.24038; PMID: 21274866
  • Nieto N, Friedman SL, Greenwel P, Cederbaum AI. CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells. Hepatology 1999; 30:987 - 96; http://dx.doi.org/10.1002/hep.510300433; PMID: 10498651
  • Jaroszewicz J, Rogalska M, Flisiak I, Flisiak R. Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C. World J Gastroenterol 2010; 16:1747 - 52; http://dx.doi.org/10.3748/wjg.v16.i14.1747; PMID: 20380007
  • Sebastiani G, Vario A, Ferrari A, Pistis R, Noventa F, Alberti A. Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C. J Viral Hepat 2006; 13:199 - 205; http://dx.doi.org/10.1111/j.1365-2893.2005.00662.x; PMID: 16475996
  • Hourioux C, Patient R, Morin A, Blanchard E, Moreau A, Trassard S, Giraudeau B, Roingeard P. The genotype 3-specific hepatitis C virus core protein residue phenylalanine 164 increases steatosis in an in vitro cellular model. Gut 2007; 56:1302 - 8; http://dx.doi.org/10.1136/gut.2006.108647; PMID: 17213339
  • Ryan JD, Altamura S, Devitt E, Mullins S, Lawless MW, Muckenthaler MU, Crowe J. Pegylated interferon-α induced hypoferremia is associated with the immediate response to treatment in hepatitis C. Hepatology 2012; 56:492 - 500; http://dx.doi.org/10.1002/hep.25666; PMID: 22334511