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Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress

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Abstract

Objective and design

The present investigation was designed to determine the effects of caffeine on alcohol-induced hepatic injury in mice.

Material

Five groups of mice (8 each) were used.

Treatment

The mice treated with different doses of caffeine (5, 10, and 20 mg/kg, respectively).

Methods

The degree of alcoholic liver injury was evaluated biochemically by measuring serum markers and pathological examination. Real time PCR and ELISA methods were used to check the expression of cytokines and CYP 450.

Results

Treatment with caffeine significantly attenuated the elevated serum aminotransferase enzymes and reduced the severe extent of hepatic cell damage, steatosis and the immigration of inflammatory cells. Interestingly, caffeine decreased hepatic mRNA expression of lipogenic genes, while it had no effect on protein expression of hepatic CYP2E1. Furthermore, caffeine decreased serum and tissue inflammatory cytokines levels, tissue lipid peroxidation and inhibited the necrosis of hepatocytes. Kupffer cells isolated from ethanol-fed mice produced high amounts of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α), whereas Kupffer cells from caffeine treatment mice produced less ROS and TNF-α.

Conclusions

These findings suggest that caffeine may represent a novel, protective strategy against alcoholic liver injury by attenuating oxidative stress and inflammatory response.

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References

  1. Williams R. Global challenges in liver disease. Hepatology. 2006;44:521–6.

    Article  PubMed  Google Scholar 

  2. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360:2758–69.

    Article  CAS  PubMed  Google Scholar 

  3. Albano E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc. 2006;65:278–90.

    Article  CAS  PubMed  Google Scholar 

  4. Arteel GE. Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology. 2003;124:778–90.

    Article  CAS  PubMed  Google Scholar 

  5. Hoek JB, Pastorino JG. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol. 2002;27:63–8.

    Article  CAS  PubMed  Google Scholar 

  6. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2009;51:307–28.

    Article  CAS  Google Scholar 

  7. O’Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol. 2010;105:14–32; quiz 33.

    Google Scholar 

  8. Dey A, Cederbaum AI. Alcohol and oxidative liver injury. Hepatology. 2006;43:S63–74.

    Article  CAS  PubMed  Google Scholar 

  9. Nagy LE. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp Biol Med (Maywood). 2003;228:882–90.

    CAS  Google Scholar 

  10. Vidali M, Stewart SF, Albano E. Interplay between oxidative stress and immunity in the progression of alcohol-mediated liver injury. Trends Mol Med. 2008;14:63–71.

    Article  CAS  PubMed  Google Scholar 

  11. Breitkopf K, Nagy LE, Beier JI, Mueller S, Weng H, Dooley S. Current experimental perspectives on the clinical progression of alcoholic liver disease. Alcohol Clin Exp Res. 2009;33:1647–55.

    Article  CAS  PubMed  Google Scholar 

  12. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology. 1999;117:942–52.

    Article  CAS  PubMed  Google Scholar 

  13. Rao R. Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology. 2009;50:638–44.

    Article  CAS  PubMed  Google Scholar 

  14. Ji C, Deng Q, Kaplowitz N. Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology. 2004;40:442–51.

    Article  CAS  PubMed  Google Scholar 

  15. Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology. 2003;124:1488–99.

    Article  CAS  PubMed  Google Scholar 

  16. Mansouri A, Gaou I, De Kerguenec C, Amsellem S, Haouzi D, Berson A, et al. An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice. Gastroenterology. 1999;117:181–90.

    Article  CAS  PubMed  Google Scholar 

  17. Yin M, Gabele E, Wheeler MD, Connor H, Bradford BU, Dikalova A, et al. Alcohol-induced free radicals in mice: direct toxicants or signaling molecules? Hepatology. 2001;34:935–42.

    Article  CAS  PubMed  Google Scholar 

  18. Barone JJ, Roberts HR. Caffeine consumption. Food Chem Toxicol. 1996;34:119–29.

    Article  CAS  PubMed  Google Scholar 

  19. Honjo S, Kono S, Coleman MP, Shinchi K, Sakurai Y, Todoroki I, et al. Coffee consumption and serum aminotransferases in middle-aged Japanese men. J Clin Epidemiol. 2001;54:823–9.

    Article  CAS  PubMed  Google Scholar 

  20. Ruhl CE, Everhart JE. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology. 2005;129:1928–36.

    Article  PubMed  Google Scholar 

  21. Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2005;128:24–32.

    Article  CAS  PubMed  Google Scholar 

  22. Tanaka K, Tokunaga S, Kono S, Tokudome S, Akamatsu T, Moriyama T, et al. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int J Epidemiol. 1998;27:438–43.

    Article  CAS  PubMed  Google Scholar 

  23. La Vecchia C. Coffee, liver enzymes, cirrhosis and liver cancer. J Hepatol. 2005;42:444–6.

    Article  CAS  PubMed  Google Scholar 

  24. Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology. 2009;51:201–9.

    Google Scholar 

  25. Cadden IS, Partovi N, Yoshida EM. Review article: possible beneficial effects of coffee on liver disease and function. Aliment Pharmacol Ther. 2007;26:1–8.

    Article  CAS  PubMed  Google Scholar 

  26. Hu G, Tuomilehto J, Pukkala E, Hakulinen T, Antikainen R, Vartiainen E, et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology. 2008;48:129–36.

    Article  PubMed  Google Scholar 

  27. Inoue M, Kurahashi N, Iwasaki M, Shimazu T, Tanaka Y, Mizokami M, et al. Effect of coffee and green tea consumption on the risk of liver cancer: cohort analysis by hepatitis virus infection status. Cancer Epidemiol Biomarkers Prev. 2009;18:1746–53.

    Article  PubMed  Google Scholar 

  28. Larsson SC, Wolk A. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007;132:1740–5.

    Article  PubMed  Google Scholar 

  29. Shimazu T, Tsubono Y, Kuriyama S, Ohmori K, Koizumi Y, Nishino Y, et al. Coffee consumption and the risk of primary liver cancer: pooled analysis of two prospective studies in Japan. Int J Cancer. 2005;116:150–4.

    Article  CAS  PubMed  Google Scholar 

  30. Back SA, Craig A, Luo NL, Ren J, Akundi RS, Ribeiro I, et al. Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol. 2006;60:696–705.

    Article  CAS  PubMed  Google Scholar 

  31. Kagami K, Morita H, Onda K, Hirano T, Oka K. Protective effect of caffeine on streptozotocin-induced beta-cell damage in rats. J Pharm Pharmacol. 2008;60:1161–5.

    Article  CAS  PubMed  Google Scholar 

  32. Akashi I, Kagami K, Hirano T, Oka K. Protective effects of coffee-derived compounds on lipopolysaccharide/d-galactosamine induced acute liver injury in rats. J Pharm Pharmacol. 2009;61:473–8.

    Article  CAS  PubMed  Google Scholar 

  33. Gressner OA, Lahme B, Rehbein K, Siluschek M, Weiskirchen R, Gressner AM. Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways. J Hepatol. 2008;49:758–67.

    Article  CAS  PubMed  Google Scholar 

  34. Gressner OA, Lahme B, Siluschek M, Gressner AM. Identification of paraxanthine as the most potent caffeine-derived inhibitor of connective tissue growth factor expression in liver parenchymal cells. Liver Int. 2009;29:886–97.

    Article  CAS  PubMed  Google Scholar 

  35. Nanji AA, Mendenhall CL, French SW. Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Exp Res. 1989;13:15–9.

    Article  CAS  PubMed  Google Scholar 

  36. Nanji AA, Su GL, Laposata M, French SW. Pathogenesis of alcoholic liver disease—recent advances. Alcohol Clin Exp Res. 2002;26:731–6.

    PubMed  Google Scholar 

  37. Garcia-Ruiz C, Colell A, Morales A, Kaplowitz N, Fernandez-Checa JC. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol. 1995;48:825–34.

    CAS  PubMed  Google Scholar 

  38. Nanji AA. Role of Kupffer cells in alcoholic hepatitis. Alcohol. 2002;27:13–5.

    Article  CAS  PubMed  Google Scholar 

  39. De Minicis S, Brenner DA. Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex. J Gastroenterol Hepatol. 2008;23(Suppl 1):S98–103.

    Article  PubMed  Google Scholar 

  40. Wu D, Cederbaum AI. Oxidative stress and alcoholic liver disease. Semin Liver Dis. 2009;29:141–54.

    Article  CAS  PubMed  Google Scholar 

  41. Arteel GE. Alcohol-induced oxidative stress in the liver: in vivo measurements. Methods Mol Biol. 2008;447:185–97.

    Article  CAS  PubMed  Google Scholar 

  42. Khanal T, Choi JH, Hwang YP, Jeong HG. Saponins isolated from the root of Platycodon grandiflorum protect against acute ethanol-induced hepatotoxicity in mice. Food Chem Toxicol. 2009;47(3):530–5.

    Google Scholar 

  43. Yoshida Y, Hayakawa M, Niki E. Evaluation of the antioxidant effects of coffee and its components using the biomarkers hydroxyoctadecadienoic acid and isoprostane. J Oleo Sci. 2008;57:691–7.

    CAS  PubMed  Google Scholar 

  44. Kamat JP, Boloor KK, Devasagayam TP, Jayashree B, Kesavan PC. Differential modification by caffeine of oxygen-dependent and independent effects of gamma-irradiation on rat liver mitochondria. Int J Radiat Biol. 2000;76:1281–8.

    Article  CAS  PubMed  Google Scholar 

  45. Lee KJ, Choi JH, Jeong HG. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachloride-induced liver damage in mice. Food Chem Toxicol. 2007;45:2118–25.

    Article  CAS  PubMed  Google Scholar 

  46. Lu Y, Cederbaum AI. CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 2008;44:723–38.

    Article  CAS  PubMed  Google Scholar 

  47. Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gabele E, et al. Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice. J Immunol. 2002;168:2963–9.

    CAS  PubMed  Google Scholar 

  48. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–80.

    Article  CAS  PubMed  Google Scholar 

  49. Goldstein DR. Toll-like receptors and other links between innate and acquired alloimmunity. Curr Opin Immunol. 2004;16:538–44.

    Article  CAS  PubMed  Google Scholar 

  50. Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, et al. Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol. 2001;166:4737–42.

    CAS  PubMed  Google Scholar 

  51. McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE. Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice. Gastroenterology. 2005;128:2066–76.

    Article  CAS  PubMed  Google Scholar 

  52. Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, et al. The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology. 2008;48:1224–31.

    Article  CAS  PubMed  Google Scholar 

  53. Bird GL, Sheron N, Goka AK, Alexander GJ, Williams RS. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med. 1990;112:917–20.

    CAS  PubMed  Google Scholar 

  54. Yun JW, Shin ES, Cho SY, Kim SH, Kim CW, Lee TR, et al. The effects of BADGE and caffeine on the time-course response of adiponectin and lipid oxidative enzymes in high fat diet-fed C57BL/6J mice: correlation with reduced adiposity and steatosis. Exp Anim. 2008;57:461–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge the support of this study by the grant from Anhui Provincial Natural Science Foundation (No 070413078) and the key Research Foundation of Higher Education of Anhui Province (No KJ2008A048) in China. We thank Dr. Hua Wang for critical reading of this manuscript.

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Authors and Affiliations

  1. School of Pharmacy, Anhui Medical University, No. 81, Meishan Road, Shushan District, Hefei, 230032, China

    Xiongwen Lv, Zhen Chen, Jun Li, Lei Zhang, Hongfeng Liu, Cheng Huang & Pengli Zhu

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  1. Xiongwen Lv
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  2. Zhen Chen
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  3. Jun Li
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  4. Lei Zhang
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  5. Hongfeng Liu
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Correspondence to Jun Li.

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Responsible Editor: L. Li.

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Lv, X., Chen, Z., Li, J. et al. Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress. Inflamm. Res. 59, 635–645 (2010). https://doi.org/10.1007/s00011-010-0176-6

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  • DOI: https://doi.org/10.1007/s00011-010-0176-6

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