Skip to main content

Role of Oxidative Stress in Alcoholic/Non-Alcoholic Liver Diseases

  • Chapter
  • First Online:
Alcoholic/Non-Alcoholic Digestive Diseases
  • 341 Accesses

Abstract

Oxidative stress is the shift in the balance between oxidants and antioxidants in favor of oxidants. Reactive oxygen species (ROS) play a central role in inducing oxidative stress. Mitochondria are the main site of cellular ROS production, and simultaneously have a well-organized antioxidant system. Therefore, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria is present to meet the demands of the cell. The liver also is the major iron storage organ in the body and therefore mild to moderate degrees of hepatic iron accumulation are sometimes involved in chronic liver diseases. Iron overload, especially excess divalent iron can be highly toxic, mainly via the Fenton reaction producing hydroxyl radicals. The liver is often a target of injury by oxidative stress. Oxidative stress has been shown to be present in alcoholic liver diseases, non-alcoholic steatohepatitis, and chronic hepatitis C to a greater degree than in other inflammatory liver diseases. This chapter highlights iron overload in the liver and mitochondrial ROS production through reduced mitochondrial quality control as important causative factors for inducing oxidative stress in chronic liver diseases, especially focusing on alcoholic liver disease, non-alcoholic steatohepatitis, and chronic hepatitis C.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. McCord JM. The evolution of free radicals and oxidative stress. Am J Med. 2000;108:652–9.

    Article  CAS  Google Scholar 

  2. Mittler R. Oxidative stress, antioxidants and stress tolerance. Trends Plant Sci. 2002;7:505–10.

    Article  Google Scholar 

  3. Sha L, Tan HY, Wang N, et al. The role of oxidative stress and antioxidants in liver disease. Int J Mol Sci. 2015;16:26087–124.

    Article  Google Scholar 

  4. Itoh K, Igarashi K, Hayashi N, et al. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol. 1995;15:4184–93.

    Article  CAS  Google Scholar 

  5. Kobayashi A, Kang MI, Okawa H, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proreosomal degradation of Nrf2. Mol Cell Biol. 2004;24:7130–9.

    Article  CAS  Google Scholar 

  6. Kobayashi A, kang MI, Watai Y, et al. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol. 2006;26:221–9.

    Article  CAS  Google Scholar 

  7. Wakabayashi N, Itoh K, Wakabayashi J, et al. keap1-null mutation leads to postnatal lethality due to constitutive NRf2 activation. Nat Genet. 2003;35:238–45.

    Article  CAS  Google Scholar 

  8. Peterson DR. Alcohol, iron-associated oxidative stress, and cancer. Alcohol. 2005;35:243–9.

    Article  Google Scholar 

  9. George DK, Goldwurm S, MacDonald GA, et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology. 1998;114:311–8.

    Article  CAS  Google Scholar 

  10. Sumida Y, Nakashima T, Yoh T, et al. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease. J Hepatol. 2003;38:32–8.

    Article  CAS  Google Scholar 

  11. Farinati F, Cardin R, De Maria N, et al. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol. 1995;22:449–56.

    Article  CAS  Google Scholar 

  12. di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR. Measurements of iron status in patients with chronic hepatitis. Gastroenterology. 1992;102:2108–13.

    Article  Google Scholar 

  13. Fenton HJH. Oxidation of tartaric acid in presence of iron. J Chem Soc. 1894;65:899–910.

    Article  CAS  Google Scholar 

  14. Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349:431–4.

    Article  CAS  Google Scholar 

  15. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–10.

    Article  CAS  Google Scholar 

  16. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102:783–8.

    Article  CAS  Google Scholar 

  17. Harrison-Findik DD, Schafer D, Klein E, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem. 2006;281:22974–82.

    Article  CAS  Google Scholar 

  18. Tavill AS, Qadri AM. Alcohol and iron. Semin Liver Dis. 2004;24:317–25.

    Article  CAS  Google Scholar 

  19. Nelson JE, Wilson L, Brunt EM, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53:448–57.

    Article  CAS  Google Scholar 

  20. Imeryuz N, Tahan V, Sonsuz A, et al. Iron preloading aggravates nutritional steatohepatitis in rats by increasing apoptotic cell death. J Hepatol. 2007;47:851–9.

    Article  CAS  Google Scholar 

  21. Nelson JE, Bhattacharya R, Lindor KD, et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology. 2007;46:723–9.

    Article  CAS  Google Scholar 

  22. Smith BW, Adams LA. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat Rev Endocrinol. 2011;7:456–65.

    Article  CAS  Google Scholar 

  23. Sorrentino P, D’Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol. 2009;50:351–7.

    Article  CAS  Google Scholar 

  24. Yanagitani A, Yamada S, Yasui S, et al. Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice. Hepatology. 2004;40:366–75.

    Article  CAS  Google Scholar 

  25. Tsuchiya H, Akechi Y, Ikeda R, et al. Suppressive effects of retinoids on iron-induced oxidative stress in the liver. Gastroenterology. 2009;136:341–350 e8.

    Article  CAS  Google Scholar 

  26. Otogawa K, Kinoshita K, Fujii H, et al. Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol. 2007;170:967–80.

    Article  CAS  Google Scholar 

  27. Hoki T, Miyanishi K, Tanaka S, et al. Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology. 2015;62:751–61.

    Article  CAS  Google Scholar 

  28. Aigner E, Theurl I, Haufe H, et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology. 2008;135:680–8.

    Article  CAS  Google Scholar 

  29. Tapryal N, Mukhopadhyay C, Das D, Fox PL, Mukhopadhyay CK. Reactive oxygen species regulate ceruloplasmin by a novel mRNA decay mechanism involving its 3′-untranslated region: implications in neurodegenerative diseases. J Biol Chem. 2009;284:1873–83.

    Article  CAS  Google Scholar 

  30. Rouault TA, Gordeuk V, Anderson G. The central role of the liver in iron storage and regulation of systemic iron homeostasis. In: Arias IM, et al., editors. The liver: biology and pathobiology. 5th ed. Hoboken: Wiley-Blackwell; 2009. p. 235–50.

    Chapter  Google Scholar 

  31. Hino K, Harada M. Metal metabolism and liver. In: Ohira H, editor. The liver in systemic diseases. Heidelberg: Springer; 2016. p. 123–33.

    Chapter  Google Scholar 

  32. Aigner E, Theurl I, Theurl M, et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr. 2008;87:1374–83.

    Article  CAS  Google Scholar 

  33. Hofer H, Osterreicher C, Jessner W, et al. Hepatic iron concentration does not predict response to standard and pegylated-IFN/ribavirin therapy in patients with chronic hepatitis C. J Hepatol. 2004;40:1018–22.

    Article  CAS  Google Scholar 

  34. Rulyak SJ, Eng SC, Patel K, McHutchison JG, Gordon SC, Kowdley KV. Relationships between hepatic iron content and virologic response in chronic hepatitis C patients treated with interferon and ribavirin. Am J Gastroenterol. 2005;100:332–7.

    Article  CAS  Google Scholar 

  35. Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection. Gastroenterology. 2003;124:1509–23.

    Article  CAS  Google Scholar 

  36. Fujita N, Sugimoto R, Takeo M, et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med. 2007;13:97–104.

    Article  CAS  Google Scholar 

  37. Girelli D, Pasino M, Goodnough JB, et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol. 2009;51:845–52.

    Article  CAS  Google Scholar 

  38. Nishina S, Hino K, Korenaga M, et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008;134:226–38.

    Article  CAS  Google Scholar 

  39. Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007;132:294–300.

    Article  CAS  Google Scholar 

  40. Migita K, Abiru S, Maeda Y, et al. Serum levels of interleukin-6 and its soluble receptors in patients with hepatitis C virus infection. Hum Immunol. 2006;67:27–32.

    Article  CAS  Google Scholar 

  41. Fisher-Wellman KH, Neufer PD. Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab. 2012;23:142–53.

    Article  CAS  Google Scholar 

  42. Williams JA, Ding WX. A mechanistic review of mitophagy and its role in protection against alcoholic liver disease. Biomol Ther. 2015;5:2619–42.

    CAS  Google Scholar 

  43. Abdelmegeed MA, Ha SK, Choi Y, Akbar M, Song BJ. Role of CYP2E1 in mitochondrial dysfunction and hepatic tissue injury in alcoholic and non-alcoholic diseases. Curr Mol Pharmacol. 2017;10:207–25.

    Article  CAS  Google Scholar 

  44. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted vis lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–51.

    Article  CAS  Google Scholar 

  45. Lambert JE. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 2014;146:726–35.

    Article  CAS  Google Scholar 

  46. Peterson RE, Kalavalapalli S, Williams CM, et al. Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity. Am J Physiol Endocrinol Metab. 2016;310:E484–94.

    Article  Google Scholar 

  47. Satapati S, Sunny NE, Kucejova E, et al. Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resitance and fatty liver. J Lipid Res. 2012;53:1081–92.

    Article  Google Scholar 

  48. Sunny NE, Bril F, Cusi K. Mitochondrial adaptation in nonalcoholic fatty liver disease: novel mechanisms and treatment strategies. Trends Endoclinol Metab. 2017;28:250–60.

    Article  CAS  Google Scholar 

  49. Satapati S, Kucejova B, Duarte JA, et al. Mitochondrial metabolism mediates oxidative stress in inflammation in fatty liver. J Clin Invest. 2015;125:4447–62.

    Article  Google Scholar 

  50. Schwer B, Ren S, Pietschmann T, et al. Targeting of hepatitis C virus core protein to mitochondria through a novel C-terminal localization motif. J Virol. 2004;78:7958–68.

    Article  CAS  Google Scholar 

  51. Korenaga M, Wang T, Li Y, et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem. 2005;280:37481–8.

    Article  CAS  Google Scholar 

  52. Tsutsumi T, Matsuda M, Aizaki H, et al. Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology. 2009;50:378–86.

    Article  CAS  Google Scholar 

  53. Li Y, Boehning DF, Qian T, Popov VL, Weinman SA. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J. 2007;21:2474–85.

    Article  CAS  Google Scholar 

  54. Piccoli C, Scrima R, Quarato G, et al. Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress. Hepatology. 2007;46:58–65.

    Article  CAS  Google Scholar 

  55. Pickles S, Vigie P, Youle R. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28:R170–85.

    Article  CAS  Google Scholar 

  56. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75.

    Article  CAS  Google Scholar 

  57. Madrigal-Matute J, Cuevro AM. Regulation of liver metabolism by autophagy. Gastroenterology. 2016;150:328–39.

    Article  CAS  Google Scholar 

  58. Maher P. Redox control of neural function: background, mechanisms, and significance. Antioxid Redox Signal. 2006;8:1941–70.

    Article  CAS  Google Scholar 

  59. Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology. 2008;46:1054–61.

    Article  Google Scholar 

  60. Hara Y, Yanatori I, Ikeda M, et al. Hepatitis C virus core protein suppresses mitophagy by interacting with Parkin in the context of mitochondrial depolarization. Am J Pathol. 2014;184:3026–39.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Keisuke Hino .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hino, K. (2019). Role of Oxidative Stress in Alcoholic/Non-Alcoholic Liver Diseases. In: Yoshiji, H., Kaji, K. (eds) Alcoholic/Non-Alcoholic Digestive Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-13-1465-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-1465-0_10

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-1464-3

  • Online ISBN: 978-981-13-1465-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics