Liver Injury and Disease Pathogenesis in Chronic Hepatitis C

  • Daisuke Yamane
  • David R. McGivern
  • Takahiro Masaki
  • Stanley M. LemonEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 369)


Chronic hepatitis C virus (HCV) infection is a leading cause of liver-specific morbidity and mortality in humans, including progressive liver fibrosis, cirrhosis, and hepatocellular carcinoma. It has also been associated with altered function in other organs, including those of the endocrine, hematopoietic, and nervous systems. Disease results from both direct regulation of cellular metabolism and signaling pathways by viral proteins as well as indirect consequences of the host response to HCV infection, including inflammatory responses stemming from immune recognition of the virus. Recent in vitro studies have begun to reveal molecular mechanisms responsible for virus-induced changes in cell metabolism and cellular kinase cascades that culminate in pathologic consequences in the liver, such as steatosis, insulin resistance, and carcinogenesis. Here we discuss how these findings may be relevant to disease pathogenesis in patients, and suggest future directions in the field.


Hepatic Stellate Cell Microsomal Triglyceride Transfer Protein Mixed Cryoglobulinemia Hepatic Stellate Cell Activation Quiescent Hepatic Stellate Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Adinolfi LE, Gambardella M, Andreana A et al (2001) Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 33:1358–1364PubMedCrossRefGoogle Scholar
  2. Agnello V, Abel G (1997) Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis Rheum 40:2007–2015PubMedCrossRefGoogle Scholar
  3. Agnello V, Chung RT, Kaplan LM (1992) A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490–1495PubMedCrossRefGoogle Scholar
  4. Ahmad J, Eng FJ, Branch AD (2011) HCV and HCC: clinical update and a review of HCC-associated viral mutations in the core gene. Semin Liver Dis 31:347–355PubMedCrossRefGoogle Scholar
  5. Akuta N, Suzuki F, Kawamura Y et al (2007) Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis. Hepatology 46:1357–1364PubMedCrossRefGoogle Scholar
  6. Alonzi T, Agrati C, Costabile B et al (2004) Steatosis and intrahepatic lymphocyte recruitment in hepatitis C virus transgenic mice. J Gen Virol 85:1509–1520PubMedCrossRefGoogle Scholar
  7. Altlparmak E, Koklu S, Yalinkilic M et al (2005) Viral and host causes of fatty liver in chronic hepatitis B. World J Gastroenterol 11:3056–3059PubMedGoogle Scholar
  8. Anderson EJ, Lustig ME, Boyle KE et al (2009) Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119:573–581PubMedCrossRefGoogle Scholar
  9. Arase Y, Suzuki F, Suzuki Y et al (2009) Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology 49:739–744PubMedCrossRefGoogle Scholar
  10. Aytug S, Reich D, Sapiro LE et al (2003) Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology 38:1384–1392PubMedGoogle Scholar
  11. Banerjee S, Saito K, Ait-Goughoulte M et al (2008) Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol 82:2606–2612PubMedCrossRefGoogle Scholar
  12. Banerjee A, Meyer K, Mazumdar B et al (2010) Hepatitis C virus differentially modulates activation of forkhead transcription factors and insulin-induced metabolic gene expression. J Virol 84:5936–5946PubMedCrossRefGoogle Scholar
  13. Barba G, Harper F, Harada T et al (1997) Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci USA 94:1200–1205PubMedCrossRefGoogle Scholar
  14. Barbaro G, Di Lorenzo G, Asti A et al (1999a) Hepatocellular mitochondrial alterations in patients with chronic hepatitis C: ultrastructural and biochemical findings. Am J Gastroenterol 94:2198–2205PubMedCrossRefGoogle Scholar
  15. Barbaro G, Di Lorenzo G, Ribersani M et al (1999b) Serum ferritin and hepatic glutathione concentrations in chronic hepatitis C patients related to the hepatitis C virus genotype. J Hepatol 30:774–782PubMedCrossRefGoogle Scholar
  16. Bataller R, Paik YH, Lindquist JN et al (2004) Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 126:529–540PubMedCrossRefGoogle Scholar
  17. Bernsmeier C, Duong FH, Christen V et al (2008) Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C. J Hepatol 49:429–440PubMedCrossRefGoogle Scholar
  18. Bonnard C, Durand A, Peyrol S et al (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118:789–800PubMedGoogle Scholar
  19. Bose SK, Shrivastava S, Meyer K et al (2012) Hepatitis C virus activates mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insulin resistance. J Virol 86:6315–6322PubMedCrossRefGoogle Scholar
  20. Boudreau HE, Emerson SU, Korzeniowska A et al (2009) Hepatitis C virus (HCV) proteins induce NADPH oxidase 4 expression in a transforming growth factor beta-dependent manner: a new contributor to HCV-induced oxidative stress. J Virol 83:12934–12946PubMedCrossRefGoogle Scholar
  21. Brenner DA (2009) Molecular pathogenesis of liver fibrosis. Trans Am Clin Climatol Assoc 120:361–368PubMedGoogle Scholar
  22. Bruno S, Crosignani A, Maisonneuve P et al (2007) Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study. Hepatology 46:1350–1356PubMedCrossRefGoogle Scholar
  23. Cacoub P, Delluc A, Saadoun D et al (2008) Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis 67:283–287PubMedCrossRefGoogle Scholar
  24. Cardin R, Saccoccio G, Masutti F et al (2001) DNA oxidative damage in leukocytes correlates with the severity of HCV-related liver disease: validation in an open population study. J Hepatol 34:587–592PubMedCrossRefGoogle Scholar
  25. Cheeseman KH, Slater TF (1993) An introduction to free radical biochemistry. Br Med Bull 49:481–493PubMedGoogle Scholar
  26. Cheng Z, Guo S, Copps K et al (2009) Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 15:1307–1311PubMedCrossRefGoogle Scholar
  27. Dal Maso L, Franceschi S (2006) Hepatitis C virus and risk of lymphoma and other lymphoid neoplasms: a meta-analysis of epidemiologic studies. Cancer Epidemiol Biomarkers Prev 15:2078–2085PubMedCrossRefGoogle Scholar
  28. Dalrymple LS, Koepsell T, Sampson J et al (2007) Hepatitis C virus infection and the prevalence of renal insufficiency. Clin J Am Soc Nephrol 2:715–721PubMedCrossRefGoogle Scholar
  29. Dammacco F, Sansonno D (1997) Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol 15:97–119PubMedCrossRefGoogle Scholar
  30. Dammacco F, Sansonno D, Cornacchiulo V et al (1993) Hepatitis C virus infection and mixed cryoglobulinemia: a striking association. Int J Clin Lab Res 23:45–49PubMedCrossRefGoogle Scholar
  31. Dammacco F, Sansonno D, Piccoli C et al (2000) The lymphoid system in hepatitis C virus infection: autoimmunity, mixed cryoglobulinemia, and Overt B-cell malignancy. Semin Liver Dis 20:143–157PubMedCrossRefGoogle Scholar
  32. de Mochel NS, Seronello S, Wang SH et al (2010) Hepatocyte NAD(P)H oxidases as an endogenous source of reactive oxygen species during hepatitis C virus infection. Hepatology 52:47–59PubMedCrossRefGoogle Scholar
  33. De Vita S, Quartuccio L, Fabris M (2008) Hepatitis C virus infection, mixed cryoglobulinemia and BLyS upregulation: targeting the infectious trigger, the autoimmune response, or both? Autoimmun Rev 8:95–99PubMedCrossRefGoogle Scholar
  34. Deng L, Adachi T, Kitayama K et al (2008) Hepatitis C virus infection induces apoptosis through a Bax-triggered, mitochondrion-mediated, caspase 3-dependent pathway. J Virol 82:10375–10385PubMedCrossRefGoogle Scholar
  35. Deng L, Shoji I, Ogawa W et al (2011) Hepatitis C virus infection promotes hepatic gluconeogenesis through an NS5A-mediated, FoxO1-dependent pathway. J Virol 85:8556–8568PubMedCrossRefGoogle Scholar
  36. Dolganiuc A, Oak S, Kodys K et al (2004) Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 127:1513–1524PubMedCrossRefGoogle Scholar
  37. Dong XC, Copps KD, Guo S et al (2008) Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 8:65–76PubMedCrossRefGoogle Scholar
  38. D’Souza R, Sabin CA, Foster GR (2005) Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol 100:1509–1515PubMedCrossRefGoogle Scholar
  39. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576PubMedCrossRefGoogle Scholar
  40. Eng FJ, Walewski JL, Klepper AL et al (2009) Internal initiation stimulates production of p8 minicore, a member of a newly discovered family of hepatitis C virus core protein isoforms. J Virol 83:3104–3114PubMedCrossRefGoogle Scholar
  41. Fabrizi F, Bruchfeld A, Mangano S et al (2007) Interferon therapy for HCV-associated glomerulonephritis: meta-analysis of controlled trials. Int J Artif Organs 30:212–219PubMedGoogle Scholar
  42. Farinati F, Cardin R, De Maria N et al (1995) Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 22:449–456PubMedCrossRefGoogle Scholar
  43. Fartoux L, Poujol-Robert A, Guechot J et al (2005) Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut 54:1003–1008PubMedCrossRefGoogle Scholar
  44. Ferri C, Marzo E, Longombardo G et al (1993) Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 81:1132–1136PubMedGoogle Scholar
  45. Ferri C, Sebastiani M, Giuggioli D et al (2004) Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 33:355–374PubMedCrossRefGoogle Scholar
  46. Fletcher NF, Yang JP, Farquhar MJ et al (2010) Hepatitis C virus infection of neuroepithelioma cell lines. Gastroenterology 139:1365–1374PubMedCrossRefGoogle Scholar
  47. Fletcher NF, Wilson GK, Murray J et al (2012) Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 142:634–643PubMedCrossRefGoogle Scholar
  48. Forton DM, Karayiannis P, Mahmud N et al (2004) Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J Virol 78:5170–5183PubMedCrossRefGoogle Scholar
  49. Forton DM, Taylor-Robinson SD, Thomas HC (2006) Central nervous system changes in hepatitis C virus infection. Eur J Gastroenterol Hepatol 18:333–338PubMedCrossRefGoogle Scholar
  50. Fox JG, Feng Y, Theve EJ et al (2010) Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens. Gut 59:88–97PubMedCrossRefGoogle Scholar
  51. Fujino T, Nakamuta M, Yada R et al (2010) Expression profile of lipid metabolism-associated genes in hepatitis C virus-infected human liver. Hepatol Res 40:923–929PubMedCrossRefGoogle Scholar
  52. Fujita N, Horiike S, Sugimoto R et al (2007) Hepatic oxidative DNA damage correlates with iron overload in chronic hepatitis C patients. Free Radic Biol Med 42:353–362PubMedCrossRefGoogle Scholar
  53. Fujita N, Sugimoto R, Ma N et al (2008) Comparison of hepatic oxidative DNA damage in patients with chronic hepatitis B and C. J Viral Hepat 15:498–507PubMedCrossRefGoogle Scholar
  54. Furutani T, Hino K, Okuda M et al (2006) Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology 130:2087–2098PubMedCrossRefGoogle Scholar
  55. Garcia-Mediavilla MV, Sanchez-Campos S, Gonzalez-Perez P et al (2005) Differential contribution of hepatitis C virus NS5A and core proteins to the induction of oxidative and nitrosative stress in human hepatocyte-derived cells. J Hepatol 43:606–613PubMedCrossRefGoogle Scholar
  56. Garcia-Ruiz I, Solis-Munoz P, Gomez-Izquierdo E et al (2012) Protein tyrosine phosphatases are involved in the interferon resistance associated with insulin resistance in HepG2 cells and obese mice. J Biol Chem 287:19564–19573PubMedCrossRefGoogle Scholar
  57. Giordano TP, Henderson L, Landgren O et al (2007) Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA 297:2010–2017PubMedCrossRefGoogle Scholar
  58. Gisbert JP, Garcia-Buey L, Pajares JM et al (2003) Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology 125:1723–1732PubMedCrossRefGoogle Scholar
  59. Gisbert JP, Garcia-Buey L, Pajares JM et al (2005) Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther 21:653–662PubMedCrossRefGoogle Scholar
  60. Gong G, Waris G, Tanveer R et al (2001) Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B. Proc Natl Acad Sci USA 98:9599–9604PubMedCrossRefGoogle Scholar
  61. Grover VP, Pavese N, Koh SB et al (2012) Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation. J Viral Hepat 19:e89–e96PubMedCrossRefGoogle Scholar
  62. Guidotti LG, Chisari FV (2006) Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23–61PubMedCrossRefGoogle Scholar
  63. Haddad J, Deny P, Munz-Gotheil C et al (1992) Lymphocytic sialadenitis of Sjogren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 339:321–323PubMedCrossRefGoogle Scholar
  64. Harris C, Herker E, Farese RV Jr et al (2011) Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis. J Biol Chem 286:42615–42625PubMedCrossRefGoogle Scholar
  65. Herker E, Harris C, Hernandez C et al (2010) Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 16:1295–1298PubMedCrossRefGoogle Scholar
  66. Hermine O, Lefrere F, Bronowicki JP et al (2002) Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347:89–94PubMedCrossRefGoogle Scholar
  67. Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456PubMedCrossRefGoogle Scholar
  68. Honda A, Arai Y, Hirota N et al (1999) Hepatitis C virus structural proteins induce liver cell injury in transgenic mice. J Med Virol 59:281–289PubMedCrossRefGoogle Scholar
  69. Hope RG, McLauchlan J (2000) Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein. J Gen Virol 81:1913–1925PubMedGoogle Scholar
  70. Houstis N, Rosen ED, Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440:944–948PubMedCrossRefGoogle Scholar
  71. Hu Z, Muroyama R, Kowatari N et al (2009) Characteristic mutations in hepatitis C virus core gene related to the occurrence of hepatocellular carcinoma. Cancer Sci 100:2465–2468PubMedCrossRefGoogle Scholar
  72. Hui JM, Sud A, Farrell GC et al (2003) Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 125:1695–1704PubMedCrossRefGoogle Scholar
  73. Hussain SP, Schwank J, Staib F et al (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26:2166–2176PubMedCrossRefGoogle Scholar
  74. Ishido S, Hotta H (1998) Complex formation of the nonstructural protein 3 of hepatitis C virus with the p53 tumor suppressor. FEBS Lett 438:258–262PubMedCrossRefGoogle Scholar
  75. Jeannot E, Boorman GA, Kosyk O et al (2012) Increased incidence of aflatoxin B1-induced liver tumors in hepatitis virus C transgenic mice. Int J Cancer 130:1347–1356PubMedCrossRefGoogle Scholar
  76. Joyce MA, Walters KA, Lamb SE et al (2009) HCV induces oxidative and ER stress, and sensitizes infected cells to apoptosis in SCID/Alb-uPA mice. PLoS Pathog 5:e1000291PubMedCrossRefGoogle Scholar
  77. Kamegaya Y, Hiasa Y, Zukerberg L et al (2005) Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis. Hepatology 41:660–667PubMedCrossRefGoogle Scholar
  78. Kanety H, Feinstein R, Papa MZ et al (1995) Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem 270:23780–23784PubMedCrossRefGoogle Scholar
  79. Kannan RP, Hensley LL, Evers LE et al (2011) Hepatitis C virus infection causes cell cycle arrest at the level of initiation of mitosis. J Virol 85:7989–8001PubMedCrossRefGoogle Scholar
  80. Kao CF, Chen SY, Chen JY et al (2004) Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein. Oncogene 23:2472–2483PubMedCrossRefGoogle Scholar
  81. Kawaguchi T, Yoshida T, Harada M et al (2004) Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol 165:1499–1508PubMedCrossRefGoogle Scholar
  82. Kawaguchi T, Ide T, Taniguchi E et al (2007) Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol 102:570–576PubMedCrossRefGoogle Scholar
  83. Kawamura T, Furusaka A, Koziel MJ et al (1997) Transgenic expression of hepatitis C virus structural proteins in the mouse. Hepatology 25:1014–1021PubMedCrossRefGoogle Scholar
  84. Kawamura H, Govindarajan S, Aswad F et al (2006) HCV core expression in hepatocytes protects against autoimmune liver injury and promotes liver regeneration in mice. Hepatology 44:936–944PubMedCrossRefGoogle Scholar
  85. Kitase A, Hino K, Furutani T et al (2005) In situ detection of oxidized n-3 polyunsaturated fatty acids in chronic hepatitis C: correlation with hepatic steatosis. J Gastroenterol 40:617–624PubMedCrossRefGoogle Scholar
  86. Kitay-Cohen Y, Amiel A, Hilzenrat N et al (2000) Bcl-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type II. Blood 96:2910–2912PubMedGoogle Scholar
  87. Klopstock N, Katzenellenbogen M, Pappo O et al (2009) HCV tumor promoting effect is dependent on host genetic background. PLoS ONE 4:e5025PubMedCrossRefGoogle Scholar
  88. Kobayashi M, Akuta N, Suzuki F et al (2010) Influence of amino-acid polymorphism in the core protein on progression of liver disease in patients infected with hepatitis C virus genotype 1b. J Med Virol 82:41–48PubMedCrossRefGoogle Scholar
  89. Korenaga M, Wang T, Li Y et al (2005) Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem 280:37481–37488PubMedCrossRefGoogle Scholar
  90. Kumar V, Kato N, Urabe Y et al (2011) Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 43:455–458PubMedCrossRefGoogle Scholar
  91. Kwun HJ, Jung EY, Ahn JY et al (2001) p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3. J Gen Virol 82:2235–2241PubMedGoogle Scholar
  92. Lan L, Gorke S, Rau SJ et al (2008) Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner. J Immunol 181:4926–4935PubMedGoogle Scholar
  93. Landau DA, Rosenzwajg M, Saadoun D et al (2009) The B lymphocyte stimulator receptor-ligand system in hepatitis C virus-induced B cell clonal disorders. Ann Rheum Dis 68:337–344PubMedCrossRefGoogle Scholar
  94. Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol 19:R1046–R1052PubMedCrossRefGoogle Scholar
  95. Leandro G, Mangia A, Hui J et al (2006) Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology 130:1636–1642PubMedCrossRefGoogle Scholar
  96. Lemon SM, McGivern DR (2012) Is hepatitis C virus carcinogenic? Gastroenterology 142:1274–1278PubMedCrossRefGoogle Scholar
  97. Lerat H, Honda M, Beard MR et al (2002) Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 122:352–365PubMedCrossRefGoogle Scholar
  98. Lerat H, Kammoun HL, Hainault I et al (2009) Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice. J Biol Chem 284:33466–33474PubMedCrossRefGoogle Scholar
  99. Li J, Rechsteiner M (2001) Molecular dissection of the 11S REG (PA28) proteasome activators. Biochimie 83:373–383PubMedCrossRefGoogle Scholar
  100. Li K, Prow T, Lemon SM et al (2002) Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells. Hepatology 35:1237–1246PubMedCrossRefGoogle Scholar
  101. Li Y, Boehning DF, Qian T et al (2007) Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. Faseb J 21:2474–2485PubMedCrossRefGoogle Scholar
  102. Liang Y, Shilagard T, Xiao SY et al (2009) Visualizing hepatitis C virus infections in human liver by two-photon microscopy. Gastroenterology 137:1448–1458PubMedCrossRefGoogle Scholar
  103. Lin W, Tsai WL, Shao RX et al (2010) Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner. Gastroenterology 138:2509–2518PubMedCrossRefGoogle Scholar
  104. Lok AS, Everhart JE, Wright EC et al (2011) Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C. Gastroenterology 140:840–849PubMedCrossRefGoogle Scholar
  105. Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307:384–387PubMedCrossRefGoogle Scholar
  106. Luedde T, Schwabe RF (2011) NF-kappaB in the liver–linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 8:108–118PubMedCrossRefGoogle Scholar
  107. Lunel F, Musset L, Cacoub P et al (1994) Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 106:1291–1300PubMedGoogle Scholar
  108. Machado MV, Oliveira AG, Cortez-Pinto H (2011) Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol 26:1361–1367PubMedGoogle Scholar
  109. Machida K, Cheng KT, Sung VM et al (2004) Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci USA 101:4262–4267PubMedCrossRefGoogle Scholar
  110. Machida K, Cheng KT, Lai CK et al (2006) Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. J Virol 80:7199–7207PubMedCrossRefGoogle Scholar
  111. Machida K, Tsukamoto H, Mkrtchyan H et al (2009) Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog. Proc Natl Acad Sci USA 106:1548–1553PubMedCrossRefGoogle Scholar
  112. Majumder M, Ghosh AK, Steele R et al (2001) Hepatitis C virus NS5A physically associates with p53 and regulates p21/waf1 gene expression in a p53-dependent manner. J Virol 75:1401–1407PubMedCrossRefGoogle Scholar
  113. Masaki T, Suzuki R, Murakami K et al (2008) Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J Virol 82:7964–7976PubMedCrossRefGoogle Scholar
  114. Mason AL, Lau JY, Hoang N et al (1999) Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 29:328–333PubMedCrossRefGoogle Scholar
  115. Mayhew CN, Carter SL, Fox SR et al (2007) RB loss abrogates cell cycle control and genome integrity to promote liver tumorigenesis. Gastroenterology 133:976–984PubMedCrossRefGoogle Scholar
  116. Mazzocca A, Sciammetta SC, Carloni V et al (2005) Binding of hepatitis C virus envelope protein E2 to CD81 up-regulates matrix metalloproteinase-2 in human hepatic stellate cells. J Biol Chem 280:11329–11339PubMedCrossRefGoogle Scholar
  117. McClendon AK, Dean JL, Ertel A et al (2011) RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage. Gastroenterology 141:1439–1450PubMedCrossRefGoogle Scholar
  118. McGivern DR, Lemon SM (2009) Tumor suppressors, chromosomal instability, and hepatitis C virus-associated liver cancer. Annu Rev Pathol 4:399–415PubMedCrossRefGoogle Scholar
  119. McGivern DR, Villanueva RA, Chinnaswamy S et al (2009) Impaired replication of hepatitis C virus containing mutations in a conserved NS5B retinoblastoma protein-binding motif. J Virol 83:7422–7433PubMedCrossRefGoogle Scholar
  120. Merkle M, Ribeiro A, Köppel S et al (2012) TLR3-dependent immune regulatory functions of human mesangial cells. Cell Mol Immunol 9:334–340PubMedCrossRefGoogle Scholar
  121. Miki D, Ochi H, Hayes CN et al (2011) Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet 43:797–800PubMedCrossRefGoogle Scholar
  122. Milward A, Mankouri J, Harris M (2010) Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion. J Gen Virol 91:373–381PubMedCrossRefGoogle Scholar
  123. Misiani R, Bellavita P, Fenili D et al (1994) Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751–756PubMedCrossRefGoogle Scholar
  124. Mitsuyoshi H, Itoh Y, Sumida Y et al (2008) Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C. Hepatol Res 38:348–353PubMedCrossRefGoogle Scholar
  125. Miyamoto H, Moriishi K, Moriya K et al (2007) Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 81:1727–1735PubMedCrossRefGoogle Scholar
  126. Miyanari Y, Atsuzawa K, Usuda N et al (2007) The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9:1089–1097PubMedCrossRefGoogle Scholar
  127. Monetti M, Levin MC, Watt MJ et al (2007) Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6:69–78PubMedCrossRefGoogle Scholar
  128. Monti G, Pioltelli P, Saccardo F et al (2005) Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 165:101–105PubMedCrossRefGoogle Scholar
  129. Moriishi K, Okabayashi T, Nakai K et al (2003) Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein. J Virol 77:10237–10249PubMedCrossRefGoogle Scholar
  130. Moriishi K, Mochizuki R, Moriya K et al (2007) Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci USA 104:1661–1666PubMedCrossRefGoogle Scholar
  131. Moriishi K, Shoji I, Mori Y et al (2010) Involvement of PA28gamma in the propagation of hepatitis C virus. Hepatology 52:411–420PubMedCrossRefGoogle Scholar
  132. Moriya K, Fujie H, Shintani Y et al (1998) The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4:1065–1067PubMedCrossRefGoogle Scholar
  133. Moriya K, Nakagawa K, Santa T et al (2001a) Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61:4365–4370PubMedGoogle Scholar
  134. Moriya K, Todoroki T, Tsutsumi T et al (2001b) Increase in the concentration of carbon 18 monounsaturated fatty acids in the liver with hepatitis C: analysis in transgenic mice and humans. Biochem Biophys Res Commun 281:1207–1212PubMedCrossRefGoogle Scholar
  135. Mousseau G, Kota S, Takahashi V et al (2011) Dimerization-driven interaction of hepatitis C virus core protein with NS3 helicase. J Gen Virol 92:101–111PubMedCrossRefGoogle Scholar
  136. Munakata T, Nakamura M, Liang Y et al (2005) Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Proc Natl Acad Sci USA 102:18159–18164PubMedCrossRefGoogle Scholar
  137. Munakata T, Liang Y, Kim S et al (2007) Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein. PLoS Pathog 3:1335–1347PubMedCrossRefGoogle Scholar
  138. Muzzi A, Leandro G, Rubbia-Brandt L et al (2005) Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol 42:41–46PubMedCrossRefGoogle Scholar
  139. Naas T, Ghorbani M, Alvarez-Maya I et al (2005) Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2. J Gen Virol 86:2185–2196PubMedCrossRefGoogle Scholar
  140. Nakamoto S, Imazeki F, Fukai K et al (2010) Association between mutations in the core region of hepatitis C virus genotype 1 and hepatocellular carcinoma development. J Hepatol 52:72–78PubMedCrossRefGoogle Scholar
  141. Oem JK, Jackel-Cram C, Li YP et al (2008) Activation of sterol regulatory element-binding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein 2. J Gen Virol 89:1225–1230PubMedCrossRefGoogle Scholar
  142. Ohata K, Hamasaki K, Toriyama K et al (2003) Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection. Cancer 97:3036–3043PubMedCrossRefGoogle Scholar
  143. Okada K, Takishita Y, Shimomura H et al (1996) Detection of hepatitis C virus core protein in the glomeruli of patients with membranous glomerulonephritis. Clin Nephrol 45:71–76PubMedGoogle Scholar
  144. Okuda M, Li K, Beard MR et al (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366–375PubMedCrossRefGoogle Scholar
  145. Pal S, Sullivan DG, Kim S et al (2006) Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism. Gastroenterology 130:1107–1116PubMedCrossRefGoogle Scholar
  146. Park CY, Choi SH, Kang SM et al (2009) Nonstructural 5A protein activates beta-catenin signaling cascades: implication of hepatitis C virus-induced liver pathogenesis. J Hepatol 51:853–864PubMedCrossRefGoogle Scholar
  147. Patton HM, Patel K, Behling C et al (2004) The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. J Hepatol 40:484–490PubMedCrossRefGoogle Scholar
  148. Pawlotsky JM, Ben Yahia M, Andre C et al (1994) Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology 19:841–848PubMedCrossRefGoogle Scholar
  149. Pekow JR, Bhan AK, Zheng H et al (2007) Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer 109:2490–2496PubMedCrossRefGoogle Scholar
  150. Pereira Tde A, Witek RP, Syn WK et al (2010) Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Invest 90:1690–1703PubMedCrossRefGoogle Scholar
  151. Perlemuter G, Sabile A, Letteron P et al (2002) Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. Faseb J 16:185–194PubMedCrossRefGoogle Scholar
  152. Persico M, Masarone M, La Mura V et al (2009) Clinical expression of insulin resistance in hepatitis C and B virus-related chronic hepatitis: differences and similarities. World J Gastroenterol 15:462–466PubMedCrossRefGoogle Scholar
  153. Polyak SJ, Khabar KS, Rezeiq M et al (2001) Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy. J Virol 75:6209–6211PubMedCrossRefGoogle Scholar
  154. Poynard T, Ratziu V, McHutchison J et al (2003) Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 38:75–85PubMedCrossRefGoogle Scholar
  155. Qadri I, Iwahashi M, Simon F (2002) Hepatitis C virus NS5A protein binds TBP and p53, inhibiting their DNA binding and p53 interactions with TBP and ERCC3. Biochim Biophys Acta 1592:193–204PubMedGoogle Scholar
  156. Qiu W, Wang X, Leibowitz B et al (2011) PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice. Hepatology 54:1249–1258PubMedCrossRefGoogle Scholar
  157. Raimondi S, Bruno S, Mondelli MU et al (2009) Hepatitis C virus genotype 1b as a risk factor for hepatocellular carcinoma development: a meta-analysis. J Hepatol 50:1142–1154PubMedCrossRefGoogle Scholar
  158. Ratziu V, Munteanu M, Charlotte F et al (2003) Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol 39:1049–1055PubMedCrossRefGoogle Scholar
  159. Rubbia-Brandt L, Leandro G, Spahr L et al (2001) Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology 39:119–124PubMedCrossRefGoogle Scholar
  160. Ryu SH, Fan X, Xu Y et al (2009) Lack of association between genotypes and subtypes of HCV and occurrence of hepatocellular carcinoma in Egypt. J Med Virol 81:844–847PubMedCrossRefGoogle Scholar
  161. Saadoun D, Suarez F, Lefrere F et al (2005) Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood 105:74–76PubMedCrossRefGoogle Scholar
  162. Saadoun D, Resche-Rigon M, Thibault V et al (2006) Antiviral therapy for hepatitis C virus–associated mixed cryoglobulinemia vasculitis: a long-term followup study. Arthritis Rheum 54:3696–3706PubMedCrossRefGoogle Scholar
  163. Saadoun D, Delluc A, Piette JC et al (2008) Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol 20:23–28PubMedGoogle Scholar
  164. Saito T, Owen DM, Jiang F et al (2008) Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454:523–527PubMedCrossRefGoogle Scholar
  165. Sansonno D, Cornacchiulo V, Iacobelli AR et al (1995) Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. Hepatology 21:305–312PubMedGoogle Scholar
  166. Sansonno D, De Vita S, Iacobelli AR et al (1998) Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol 160:3594–3601PubMedGoogle Scholar
  167. Sansonno D, Lauletta G, Nisi L et al (2003) Non-enveloped HCV core protein as constitutive antigen of cold-precipitable immune complexes in type II mixed cryoglobulinaemia. Clin Exp Immunol 133:275–282PubMedCrossRefGoogle Scholar
  168. Sato Y, Kato J, Takimoto R et al (2006) 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 55:1801–1808PubMedCrossRefGoogle Scholar
  169. Schulze-Krebs A, Preimel D, Popov Y et al (2005) Hepatitis C virus-replicating hepatocytes induce fibrogenic activation of hepatic stellate cells. Gastroenterology 129:246–258PubMedCrossRefGoogle Scholar
  170. Sène D, Limal N, Cacoub P (2004) Hepatitis C virus-associated extrahepatic manifestations: a review. Metab Brain Dis 19:357–381PubMedCrossRefGoogle Scholar
  171. Seto WK, Lai CL, Fung J et al (2010) Natural history of chronic hepatitis C: genotype 1 versus genotype 6. J Hepatol 53:444–448PubMedCrossRefGoogle Scholar
  172. Shi ST, Polyak SJ, Tu H et al (2002) Hepatitis C virus NS5A colocalizes with the core protein on lipid droplets and interacts with apolipoproteins. Virology 292:198–210PubMedCrossRefGoogle Scholar
  173. Shintani Y, Fujie H, Miyoshi H et al (2004) Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126:840–848PubMedCrossRefGoogle Scholar
  174. Shirakura M, Murakami K, Ichimura T et al (2007) E6AP ubiquitin ligase mediates ubiquitylation and degradation of hepatitis C virus core protein. J Virol 81:1174–1185PubMedCrossRefGoogle Scholar
  175. Simo R, Lecube A, Genesca J et al (2006) Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care 29:2462–2466PubMedCrossRefGoogle Scholar
  176. Stokes MB, Chawla H, Brody RI et al (1997) Immune complex glomerulonephritis in patients coinfected with human immunodeficiency virus and hepatitis C virus. Am J Kidney Dis 29:514–525PubMedCrossRefGoogle Scholar
  177. Storozhevykh TP, Senilova YE, Persiyantseva NA et al (2007) Mitochondrial respiratory chain is involved in insulin-stimulated hydrogen peroxide production and plays an integral role in insulin receptor autophosphorylation in neurons. BMC Neurosci 8:84PubMedCrossRefGoogle Scholar
  178. Street A, Macdonald A, McCormick C et al (2005) Hepatitis C virus NS5A-mediated activation of phosphoinositide 3-kinase results in stabilization of cellular beta-catenin and stimulation of beta-catenin-responsive transcription. J Virol 79:5006–5016PubMedCrossRefGoogle Scholar
  179. Su AI, Pezacki JP, Wodicka L et al (2002) Genomic analysis of the host response to hepatitis C virus infection. Proc Natl Acad Sci USA 99:15669–15674PubMedCrossRefGoogle Scholar
  180. Sun B, Karin M (2008) NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene 27:6228–6244PubMedCrossRefGoogle Scholar
  181. Suzuki R, Moriishi K, Fukuda K et al (2009) Proteasomal turnover of hepatitis C virus core protein is regulated by two distinct mechanisms: a ubiquitin-dependent mechanism and a ubiquitin-independent but PA28gamma-dependent mechanism. J Virol 83:2389–2392PubMedCrossRefGoogle Scholar
  182. Tai DI, Tsai SL, Chen YM et al (2000) Activation of nuclear factor kappaB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis. Hepatology 31:656–664PubMedCrossRefGoogle Scholar
  183. Tanaka M, Nagano-Fujii M, Deng L et al (2006) Single-point mutations of hepatitis C virus NS3 that impair p53 interaction and anti-apoptotic activity of NS3. Biochem Biophys Res Commun 340:792–799PubMedCrossRefGoogle Scholar
  184. Tanaka N, Moriya K, Kiyosawa K et al (2008) PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest 118:683–694PubMedGoogle Scholar
  185. Taniguchi H, Kato N, Otsuka M et al (2004) Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. J Med Virol 72:52–59PubMedCrossRefGoogle Scholar
  186. Thoren F, Romero A, Lindh M et al (2004) A hepatitis C virus-encoded, nonstructural protein (NS3) triggers dysfunction and apoptosis in lymphocytes: role of NADPH oxidase-derived oxygen radicals. J Leukoc Biol 76:1180–1186PubMedCrossRefGoogle Scholar
  187. Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339–346PubMedCrossRefGoogle Scholar
  188. Tsutsumi T, Matsuda M, Aizaki H et al (2009) Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology 50:378–386PubMedCrossRefGoogle Scholar
  189. Veldt BJ, Chen W, Heathcote EJ et al (2008) Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 47:1856–1862PubMedCrossRefGoogle Scholar
  190. Walters KA, Syder AJ, Lederer SL et al (2009) Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes. PLoS Pathog 5:e1000269PubMedCrossRefGoogle Scholar
  191. Wang D, Sul HS (1998) Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J Biol Chem 273:25420–25426PubMedCrossRefGoogle Scholar
  192. Wang AG, Lee DS, Moon HB et al (2009a) Non-structural 5A protein of hepatitis C virus induces a range of liver pathology in transgenic mice. J Pathol 219:253–262PubMedCrossRefGoogle Scholar
  193. Wang CS, Yao WJ, Chang TT et al (2009b) The impact of type 2 diabetes on the development of hepatocellular carcinoma in different viral hepatitis statuses. Cancer Epidemiol Biomarkers Prev 18:2054–2060PubMedCrossRefGoogle Scholar
  194. Wang N, Liang Y, Devaraj S et al (2009c) Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. J Virol 83:9824–9834PubMedCrossRefGoogle Scholar
  195. Waris G, Tardif KD, Siddiqui A (2002) Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. Biochem Pharmacol 64:1425–1430PubMedCrossRefGoogle Scholar
  196. Waris G, Livolsi A, Imbert V et al (2003) Hepatitis C virus NS5A and subgenomic replicon activate NF-kappaB via tyrosine phosphorylation of IkappaBalpha and its degradation by calpain protease. J Biol Chem 278:40778–40787PubMedCrossRefGoogle Scholar
  197. Waris G, Felmlee DJ, Negro F et al (2007) Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol 81:8122–8130PubMedCrossRefGoogle Scholar
  198. Westin J, Lagging M, Dhillon AP et al (2007) Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection. J Viral Hepat 14:29–35PubMedCrossRefGoogle Scholar
  199. Wörnle M, Schmid H, Banas B et al (2006) Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis. Am J Pathol 168:370–385PubMedCrossRefGoogle Scholar
  200. Xu J, Kim HT, Ma Y et al (2008) Trauma and hemorrhage-induced acute hepatic insulin resistance: dominant role of tumor necrosis factor-alpha. Endocrinology 149:2369–2382PubMedCrossRefGoogle Scholar
  201. Yamaguchi A, Tazuma S, Nishioka T et al (2005) Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci 50:1361–1371PubMedCrossRefGoogle Scholar
  202. Yamaji S, Zhang M, Zhang J et al (2010) Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis. Proc Natl Acad Sci USA 107:22237–22242PubMedCrossRefGoogle Scholar
  203. Yu T, Robotham JL, Yoon Y (2006) Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA 103:2653–2658PubMedCrossRefGoogle Scholar
  204. Zhang J, Gao Z, Yin J et al (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem 283:35375–35382PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Daisuke Yamane
    • 1
  • David R. McGivern
    • 1
  • Takahiro Masaki
    • 1
  • Stanley M. Lemon
    • 2
    Email author
  1. 1.Lineberger Comprehensive Cancer Center, Division of Infectious Diseases, Department of Medicine, and the Department of Microbiology and ImmunologyThe University of North Carolina at Chapel HillChapel HillUSA
  2. 2.8.034 Burnett-WomackThe University of North Carolina at Chapel HillChapel HillUSA

Personalised recommendations