Journal of Hepatology
Volume 54, Issue 1 , Pages 142-152 , January 2011

Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C

  • Carmelo García-Monzón

      Affiliations

    • Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Oreste Lo Iacono

      Affiliations

    • Gastroenterology Unit, Hospital del Tajo, Aranjuez, Madrid, Spain
    • ,
  • Rafael Mayoral

      Affiliations

    • Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (IIBM-CSIC-UAM), Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Águeda González-Rodríguez

      Affiliations

    • Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (IIBM-CSIC-UAM), Madrid, Spain
    • Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Spain
    • ,
  • María E. Miquilena-Colina

      Affiliations

    • Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Tamara Lozano-Rodríguez

      Affiliations

    • Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Leonor García-Pozo

      Affiliations

    • Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Javier Vargas-Castrillón

      Affiliations

    • Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Marta Casado

      Affiliations

    • Instituto de Biomedicina de Valencia, IBV-CSIC, Valencia, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Lisardo Boscá

      Affiliations

    • Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (IIBM-CSIC-UAM), Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • ,
  • Ángela M. Valverde

      Affiliations

    • Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (IIBM-CSIC-UAM), Madrid, Spain
    • Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Spain
    • Corresponding Author InformationCorresponding author. Address: Instituto de Investigaciones Biomédicas “Alberto Sols” IIBM, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain.
    • These two authors share senior authorship.
    • ,
  • Paloma Martín-Sanz

      Affiliations

    • Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid (IIBM-CSIC-UAM), Madrid, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
    • Corresponding Author InformationCorresponding author. Address: Instituto de Investigaciones Biomédicas “Alberto Sols” IIBM, CSIC-UAM, Arturo Duperier, 4, 28029 Madrid, Spain. Fax: +34 91 4972748.
    • These two authors share senior authorship.

Received 19 January 2010 ,Revised 6 May 2010 ,Accepted 8 June 2010.

References 

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231
  2. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41–52
  3. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987–1000
  4. Larter CZ, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH: which is the best target to treat?. J Hepatol. 2006;44:253–261
  5. Previs SF, Withers DJ, Ren JM, White MF, Shulman GI. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem. 2000;275:38990–38994
  6. Valverde AM, Burks DJ, Fabregat I, Fisher TL, Carretero J, White MF, et al. Molecular mechanisms of insulin resistance in IRS-2-deficient hepatocytes. Diabetes. 2003;52:2239–2248
  7. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152
  8. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–138
  9. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923
  10. Romero-Gomez M. Insulin resistance and hepatitis C. World J Gastroenterol. 2006;12:7075–7080
  11. Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134:416–423
  12. Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641
  13. Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137:532–540
  14. Everhart JE, Lok AS, Kim HY, Morgan TR, Lindsay KL, Chung RT, et al. Weight related effects on disease progression in the hepatitis c antiviral long-term treatment against cirrhosis trial. Gastroenterology. 2009;137:549–557
  15. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–2474
  16. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321
  17. Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991;13:372–374
  18. Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C, et al. Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol. 1998;72:3691–3697
  19. Núñez O, Fernández-Martínez A, Majano PL, Apolinario A, Gómez-Gonzalo M, Benedicto I, et al. Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins. Gut. 2004;53:1665–1672
  20. Long YC, Zierath JR. AMP-activated protein kinase signalling in metabolic regulation. J Clin Invest. 2006;116:1776–1783
  21. Frescas D, Valenti L, Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem. 2005;280:20589–20595
  22. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–218
  23. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–1850
  24. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem. 2004;279:32345–32353
  25. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab. 2007;6:69–78
  26. Zhang X, Yang J, Guo Y, Ye H, Yu C, Xu C, et al. Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: Enoyl–Coenzyme A hydratase down-regulation exacerbates hepatic steatosis. Hepatology. 2010;51:1190–1199
  27. Kantartzis K, Machicao F, Machann J, Schick F, Fritsche A, Häring HU, et al. The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans. Clin Sci (Lond.). 2009;116:531–537
  28. Kantartzis K, Peter A, Machicao F, Machann J, Wagner S, Königsrainer I, et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes. 2009;58:2616–2623
  29. Valenti L, Rametta R, Dongiovanni P, Maggioni M, Francanzani AL, Zappa M, et al. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes. 2008;57:1355–1362
  30. Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848
  31. Fisher TL, White MF. Signalling pathways: the benefits of good communication. Curr Biol. 2004;14:R1005–R1007
  32. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55:S9–S15
  33. Solinas G, Naugler W, Galimi F, Lee MS, Karin M. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc Natl Acad Sci USA. 2006;103:16454–16459
  34. Banerjee S, Saito K, Ait-Goughoulte M, Meyer K, Ray RB, Ray R. Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signalling pathway for insulin resistance. J Virol. 2008;82:2606–2612
  35. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–443
  36. Walsh MJ, Vanags DM, Clouston AD, Richardson MM, Purdie DM, Jonsson JR, et al. Steatosis and liver cell apoptosis in chronic hepatitis C: a mechanism for increased liver injury. Hepatology. 2004;39:1230–1238
  37. Navarro P, Valverde AM, Benito M, Lorenzo M. Insulin/IGF-I rescues immortalized brown adipocytes from apoptosis down-regulating Bcl-xS expression, in a PI 3-kinase and MAP kinase-dependent manner. Exp Cell Res. 1998;243:213–221
  38. Valverde AM, Fabregat I, Burks DJ, White MF, Benito M. IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes. Hepatology. 2004;40:1285–1294
  39. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669
  40. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest. 2003;83:655–663
  41. Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, Bronk SF, et al. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology. 2003;38:1188–1198
  42. Svegliati-Baroni G, Ridolfi F, Di Sario A, Casini A, Marucci L, Gaggiotti G, et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology. 1999;29:1743–1751

PII: S0168-8278(10)00711-7

doi: 10.1016/j.jhep.2010.06.021

Journal of Hepatology
Volume 54, Issue 1 , Pages 142-152 , January 2011

Article Tools

* Image Usage & Resolution