Movatterモバイル変換

[0]ホーム
URL:

Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advertisement

Nature Protocols
  • Protocol
  • Published:

Mouse model of chronic and binge ethanol feeding (the NIAAA model)

Nature Protocolsvolume 8, pages627–637 (2013)Cite this article

Subjects

Abstract

Chronic alcohol consumption is a leading cause of chronic liver disease worldwide, leading to cirrhosis and hepatocellular carcinoma. Currently, the most widely used model for alcoholic liver injury isad libitum feeding with the Lieber-DeCarli liquid diet containing ethanol for 4–6 weeks; however, this model, without the addition of a secondary insult, only induces mild steatosis, slight elevation of serum alanine transaminase (ALT) and little or no inflammation. Here we describe a simple mouse model of alcoholic liver injury by chronic ethanol feeding (10-dad libitum oral feeding with the Lieber-DeCarli ethanol liquid diet) plus a single binge ethanol feeding. This protocol for chronic-plus-single-binge ethanol feeding synergistically induces liver injury, inflammation and fatty liver, which mimics acute-on-chronic alcoholic liver injury in patients. This feeding protocol can also be extended to chronic feeding for longer periods of time up to 8 weeks plus single or multiple binges. Chronic-binge ethanol feeding leads to high blood alcohol levels; thus, this simple model will be very useful for the study of alcoholic liver disease (ALD) and of other organs damaged by alcohol consumption.

This is a preview of subscription content,access via your institution

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

￥ 4,980

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of the NIAAA model procedure.
Figure 2: Cage and feeding-tube setup.
Figure 3: Oral gavage.
Figure 4: Body weight changes during the chronic-plus-binge ethanol feeding model.
Figure 5: Hepatic expression of CYP2E1 and plasma ethanol levels post ethanol feeding.
Figure 6: Comparison of liver injury induced by the chronic-plus-single-binge ethanol feeding model and other feeding models.

Similar content being viewed by others

References

  1. Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology141, 1572–1585 (2011).

    Article CAS  Google Scholar 

  2. Tsukamoto, H. & Lu, S.C. Current concepts in the pathogenesis of alcoholic liver injury.FASEB J.15, 1335–1349 (2001).

    Article CAS  Google Scholar 

  3. O'Shea, R.S., Dasarathy, S. & McCullough, A.J. Practice Guideline Committee of the American Association for the Study of Liver, D. & Practice Parameters Committee of the American College of, G. Alcoholic liver disease.Hepatology51, 307–328 (2010).

    Article  Google Scholar 

  4. Stickel, F. & Seitz, H.K. Alcoholic steatohepatitis.Best Pract. Res. Clin. Gastroenterol.24, 683–693 (2010).

    Article CAS  Google Scholar 

  5. Beier, J.I., Arteel, G.E. & McClain, C.J. Advances in alcoholic liver disease.Curr. Gastroenterol. Rep.13, 56–64 (2011).

    Article  Google Scholar 

  6. Bellentani, S . et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group.Gut41, 845–850 (1997).

    Article CAS  Google Scholar 

  7. Stranges, S. et al. Differential effects of alcohol drinking pattern on liver enzymes in men and women.Alcohol. Clin. Exp. Res.28, 949–956 (2004).

    Article CAS  Google Scholar 

  8. Li, T.K. Quantifying the risk for alcohol-use and alcohol-attributable health disorders: present findings and future research needs.J. Gastroenterol. Hepatol.23 (suppl. 1), S2–S8 (2008).

    Article CAS  Google Scholar 

  9. Ki, S.H. et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3.Hepatology52, 1291–1300 (2010).

    Article CAS  Google Scholar 

  10. Mathurin, P. & Lucey, M.R. Management of alcoholic hepatitis.J. Hepatol.56 (suppl. 1), S39–S45 (2012).

    Article CAS  Google Scholar 

  11. Choi, G. & Runyon, B.A. Alcoholic hepatitis: a clinician's guide.Clin. Liver Dis.16, 371–385 (2012).

    Article  Google Scholar 

  12. Altamirano, J. & Bataller, R. Alcoholic liver disease: pathogenesis and new targets for therapy.Nat. Rev. Gastroenterol. and Hepatol.8, 491–501 (2011).

    Article CAS  Google Scholar 

  13. Aroor, A.R., Jackson, D.E. & Shukla, S.D. Elevated activation of ERK1 and ERK2 accompany enhanced liver injury following alcohol binge in chronically ethanol-fed rats.Alcohol. Clin. Exp. Res.35, 2128–2138 (2011).

    Article CAS  Google Scholar 

  14. Petrasek, J. et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.J. Clin. Invest.122, 3476–3489 (2012).

    Article CAS  Google Scholar 

  15. Cohen, J.I., Roychowdhury, S., McMullen, M.R., Stavitsky, A.B. & Nagy, L.E. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice.Gastroenterology139, 664–674 (2010).

    Article CAS  Google Scholar 

  16. Mandrekar, P., Ambade, A., Lim, A., Szabo, G. & Catalano, D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice.Hepatology54, 2185–2197 (2011).

    Article CAS  Google Scholar 

  17. Nath, B. et al. Hepatocyte-specific hypoxia-inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice.Hepatology53, 1526–1537 (2011).

    Article CAS  Google Scholar 

  18. Hu, M. et al. Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice.Hepatology55, 437–446 (2012).

    Article CAS  Google Scholar 

  19. Liangpunsakul, S. et al. Imipramine blocks ethanol-induced ASMase activation, ceramide generation, and PP2A activation, and ameliorates hepatic steatosis in ethanol-fed mice.Am. J. Physiol. Gastrointest. Liver Physiol.302, G515–523 (2012).

    Article CAS  Google Scholar 

  20. Leung, T.M. et al. Argininosuccinate synthase conditions the response to acute and chronic ethanol-induced liver injury in mice.Hepatology55, 1596–1609 (2012).

    Article  Google Scholar 

  21. Zhou, Z. et al. Zinc supplementation prevents alcoholic liver injury in mice through attenuation of oxidative stress.Am. J. Pathol.166, 1681–1690 (2005).

    Article CAS  Google Scholar 

  22. Ueno, A. et al. Mouse intragastric infusion (iG) model.Nat. Protoc.7, 771–781 (2012).

    Article CAS  Google Scholar 

  23. Xu, J. et al. Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK.J. Hepatol.55, 673–682 (2011).

    Article CAS  Google Scholar 

  24. Tsukamoto, H. et al. Severe and progressive steatosis and focal necrosis in rat liver induced by continuous intragastric infusion of ethanol and low fat diet.Hepatology5, 224–232 (1985).

    Article CAS  Google Scholar 

  25. Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis.Proc. Natl. Acad. Sci. USA109, 9448–9453 (2012).

    Article CAS  Google Scholar 

  26. Zhou, Z. et al. A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-α production.Am. J. Pathol.163, 1137–1146 (2003).

    Article CAS  Google Scholar 

  27. Zhou, Z., Sun, X. & James Kang, Y. Metallothionein protection against alcoholic liver injury through inhibition of oxidative stress.Exp. Biol. Med.227, 214–222 (2002).

    Article CAS  Google Scholar 

  28. Beier, J.I., Kaiser, J.P., Guo, L., Martinez-Maldonado, M. & Arteel, G.E. Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis.Arch. Biochem. Biophys.510, 19–26 (2011).

    Article CAS  Google Scholar 

  29. Kao, E., Shinohara, M., Feng, M., Lau, M.Y. & Ji, C. Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes.Hepatology56, 594–604 (2012).

    Article CAS  Google Scholar 

  30. Cook, R.T. et al. Thymocytes, pre-B cells, and organ changes in a mouse model of chronic ethanol ingestion–absence of subset-specific glucocorticoid-induced immune cell loss.Alcohol. Clin. Exp. Res.31, 1746–1758 (2007).

    Article CAS  Google Scholar 

  31. Meadows, G.G., Blank, S.E. & Duncan, D.D. Influence of ethanol consumption on natural killer cell activity in mice.Alcohol. Clin. Exp. Res.13, 476–479 (1989).

    Article CAS  Google Scholar 

  32. Coleman, R.A., Young, B.M., Turner, L.E. & Cook, R.T. A practical method of chronic ethanol administration in mice.Methods Mol. Biol.447, 49–59 (2008).

    Article CAS  Google Scholar 

  33. Brandon-Warner, E., Schrum, L.W., Schmidt, C.M. & McKillop, I.H. Rodent models of alcoholic liver disease: Of mice and men.Alcohol46, 715–725 (2012).

    Article  Google Scholar 

  34. Brandon-Warner, E., Walling, T.L., Schrum, L.W. & McKillop, I.H. Chronic ethanol feeding accelerates hepatocellular carcinoma progression in a sex-dependent manner in a mouse model of hepatocarcinogenesis.Alcohol. Clin. Exp. Res.36, 641–653 (2012).

    Article CAS  Google Scholar 

  35. Gabele, E. et al. A new model of interactive effects of alcohol and high-fat diet on hepatic fibrosis.Alcohol. Clin. Exp. Res.35, 1361–1367 (2011).

    Article  Google Scholar 

  36. Wei, V.L. & Singh, S.M. Genetically determined response of hepatic aldehyde dehydrogenase activity to ethanol exposures may be associated with alcohol sensitivity in mouse genotypes.Alcohol. Clin. Exp. Res.12, 39–45 (1988).

    Article CAS  Google Scholar 

  37. You, M., Considine, R.V., Leone, T.C., Kelly, D.P. & Crabb, D.W. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice.Hepatology42, 568–577 (2005).

    Article CAS  Google Scholar 

  38. Everitt, H. et al. Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice.Am. J. Physiol. Gastrointest. Liver Physiol.304, G38–G47 (2013).

    Article CAS  Google Scholar 

  39. Tsuchiya, M. et al. Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice.Hepatology56, 130–139 (2012).

    Article CAS  Google Scholar 

  40. Butura, A. et al. The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model.J. Hepatol.50, 572–583 (2009).

    Article CAS  Google Scholar 

  41. Lu, Y., Zhuge, J., Wang, X., Bai, J. & Cederbaum, A.I. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice.Hepatology47, 1483–1494 (2008).

    Article CAS  Google Scholar 

  42. Kono, H. et al. Gender differences in early alcohol-induced liver injury: role of CD14, NF-κB, and TNF-α.Am. J. Physiol. Gastrointest. Liver Physiol.278, G652–G661 (2000).

    Article CAS  Google Scholar 

  43. Nanji, A.A. et al. Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.Am. J. Physiol. Gastrointest. Liver Physiol.281, G1348–G1356 (2001).

    Article CAS  Google Scholar 

  44. Kirpich, I.A. et al. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease.Alcohol. Clin. Exp. Res.36, 835–846 (2012).

    Article CAS  Google Scholar 

Download references

Acknowledgements

We greatly appreciate all current and previous lab members for their technical support and helpful discussions. We also thank L. Chedester, A. Barnes and R. Kechrid from the Office of Laboratory Animal Science for their technical and engineering support, and for their critical reading of the manuscript. This work is supported by the intramural program of NIAAA at the NIH.

Author information

Authors and Affiliations

  1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, Maryland, USA

    Adeline Bertola, Stephanie Mathews, Sung Hwan Ki, Hua Wang & Bin Gao

Authors
  1. Adeline Bertola
  2. Stephanie Mathews
  3. Sung Hwan Ki
  4. Hua Wang
  5. Bin Gao

Contributions

A.B. contributed to generating the data presented, making the figures and tables and drafting the procedures; S.M. contributed to drafting the materials and generating data presented inFigure 4; S.H.K. and H.W. contributed to generating the data presented inFigure 4 and B.G. contributed to drafting and the completion of the manuscript through supervision of others.

Corresponding author

Correspondence toBin Gao.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

About this article

Cite this article

Bertola, A., Mathews, S., Ki, S.et al. Mouse model of chronic and binge ethanol feeding (the NIAAA model).Nat Protoc8, 627–637 (2013). https://doi.org/10.1038/nprot.2013.032

Download citation

This article is cited by

Access through your institution
Buy or subscribe

Advertisement

Search

Advanced search

Quick links

Nature Briefing

Sign up for theNature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox.Sign up for Nature Briefing
[8]ページ先頭
©2009-2026 Movatter.jp