Hepatology International

, Volume 8, Supplement 2, pp 475–480 | Cite as

New drug targets for alcoholic liver disease

  • Mingjiang Xu
  • Binxia Chang
  • Stephanie Mathews
  • Bin GaoEmail author
Supplement Issue: ALPD


Alcoholic liver disease (ALD) represents a spectrum of disorders, ranging from simple steatosis to severe alcoholic hepatitis and cirrhosis. The severe form of ALD comprises multiple problems in the liver, including inflammation, hepatocellular damage, fibrosis, and impaired liver regeneration, and likely requires combinational therapies. In this review, we discuss recently identified therapeutic targets that inhibit inflammation, ameliorate hepatocyte death, and promote liver repair in ALD, with a focus on our recent studies on the immunosuppressive drug prednisolone and the hepatoprotective cytokine interleukin-22. Clinical trials examining prednisolone plus interleukin-22 therapy for severe alcoholic hepatitis are currently under consideration.


Prednisolone Interleukin-22 Inflammation Liver Ethanol 


Compliance with ethical requirements and Conflict of interest

Mingjiang Xu, Binxia Chang, Stephanie Mathews, and Bin Gao have nothing to disclose. This article does not contain any studies with human or animal subjects.


  1. 1.
    Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572–1585PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Wang HJ, Gao B, Zakhari S, Nagy LE. Inflammation in alcoholic liver disease. Annu Rev Nutr 2012;32:343–368PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360:2758–2769PubMedCrossRefGoogle Scholar
  4. 4.
    Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut 2011;60:255–260PubMedCrossRefGoogle Scholar
  5. 5.
    Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011;365:1781–1789PubMedCrossRefGoogle Scholar
  6. 6.
    Singal AK, Shah VH. Alcoholic hepatitis: prognostic models and treatment. Gastroenterol Clin North Am 2011;40:611–639PubMedCrossRefGoogle Scholar
  7. 7.
    Christensen E. Glucocorticosteroids in acute alcoholic hepatitis: the evidence of a beneficial effect is getting even weaker. J Hepatol 2010;53:390–391PubMedCrossRefGoogle Scholar
  8. 8.
    Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875–879PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Cox G. Glucocorticoid treatment inhibits apoptosis in human neutrophils. Separation of survival and activation outcomes. J Immunol 1995;154:4719–4725PubMedGoogle Scholar
  10. 10.
    Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653–658PubMedCrossRefGoogle Scholar
  11. 11.
    Lin F, Taylor NJ, Su H, Huang X, Hussain MJ, Abeles RD, et al. Alcohol dehydrogenase-specific T-cell responses are associated with alcohol consumption in patients with alcohol-related cirrhosis. Hepatology 2013;58:314–324PubMedCrossRefGoogle Scholar
  12. 12.
    Tanner AR, Powell LW. Corticosteroids in liver disease: possible mechanisms of action, pharmacology, and rational use. Gut 1979;20:1109–1124PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Kwon HJ, Won YS, Park O, Feng D, Gao B. Opposing effects of prednisolone treatment on T/NKT cell- and hepatotoxin-mediated hepatitis in mice. Hepatology 2013;. doi: 10.1002/hep.26748 PubMedGoogle Scholar
  14. 14.
    Dominguez M, Miquel R, Colmenero J, Moreno M, Garcia-Pagan JC, Bosch J, et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 2009;136:1639–1650PubMedCrossRefGoogle Scholar
  15. 15.
    Colmenero J, Bataller R, Sancho-Bru P, Bellot P, Miquel R, Moreno M, et al. Hepatic expression of candidate genes in patients with alcoholic hepatitis: correlation with disease severity. Gastroenterology 2007;132:687–697PubMedCrossRefGoogle Scholar
  16. 16.
    Bertola A, Park O, Gao B. Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury: a critical role for E-selectin. Hepatology 2013;58:1814–1823PubMedCrossRefGoogle Scholar
  17. 17.
    Adams DH, Hubscher SG, Fisher NC, Williams A, Robinson M. Expression of E-selectin and E-selectin ligands in human liver inflammation. Hepatology 1996;24:533–538PubMedCrossRefGoogle Scholar
  18. 18.
    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. Hepatology 2011;54:2185–2197PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Urtasun R, Lopategi A, George J, Leung TM, Lu Y, Wang X, et al. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin alpha(V)beta(3) engagement and PI3K/pAkt/NFkappaB signaling. Hepatology 2012;55:594–608PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Pritchett J, Harvey E, Athwal V, Berry A, Rowe C, Oakley F, et al. Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans. Hepatology 2012;56:1108–1116PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Morales-Ibanez O, Dominguez M, Ki SH, Marcos M, Chaves JF, Nguyen-Khac E, et al. Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. Hepatology 2013;58:1742–1756PubMedCrossRefGoogle Scholar
  22. 22.
    Ge X, Leung TM, Arriazu E, Lu Y, Urtasun R, Christensen B, et al. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-alpha and prevents early alcohol-induced liver injury in mice. Hepatology 2013;. doi: 10.1002/hep.26931 Google Scholar
  23. 23.
    Lazaro R, Ueno A, Do R, Zhu L, Wu R, Xu J, et al. Mouse model of alcoholic hepatitis: no role of osteopontin. Hepatology 2013;58:834AGoogle Scholar
  24. 24.
    Hartmann P, Chen WC, Schnabl B. The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease. Front Physiol 2012;3:402PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology 2013;58:108–119PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Yan AW, Fouts DE, Brandl J, Starkel P, Torralba M, Schott E, et al. Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 2011;53:96–105PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Pritchard MT, McMullen MR, Medof ME, Stavitsky A, Nagy LE. Role of complement in ethanol-induced liver injury. Adv Exp Med Biol 2008;632:175–186PubMedGoogle Scholar
  28. 28.
    Mathews S, Gao B. Therapeutic potential of interleukin 1 inhibitors in the treatment of alcoholic liver disease. Hepatology 2013;57:2078–2080PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 2012;122:3476–3489PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Jung Y, Brown KD, Witek RP, Omenetti A, Yang L, Vandongen M, et al. Accumulation of hedgehog-responsive progenitors parallels alcoholic liver disease severity in mice and humans. Gastroenterology 2008;134:1532–1543PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Sancho-Bru P, Altamirano J, Rodrigo-Torres D, Coll M, Millan C, Jose Lozano J, et al. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology 2012;55:1931–1941PubMedCrossRefGoogle Scholar
  32. 32.
    Gao B. Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease. J Gastroenterol Hepatol 2012;27(Suppl 2):89–93PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Kong X, Feng D, Wang H, Hong F, Bertola A, Wang FS, et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 2012;56:1150–1159PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012;143:765–776Google Scholar
  35. 35.
    Radaeva S, Sun R, Pan HN, Hong F, Gao B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 2004;39:1332–1342PubMedCrossRefGoogle Scholar
  36. 36.
    Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R. 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. Hepatology 2010;52:1291–1300PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Rubino SJ, Geddes K, Girardin SE. Innate IL-17 and IL-22 responses to enteric bacterial pathogens. Trends Immunol 2012;33:112–118PubMedCrossRefGoogle Scholar
  38. 38.
    Xu M, Feng D, Wang H, Guan Y, Yan X, Gao B. Interleukin-22 ameliorates renal ischemia-reperfusion injury via the activation of STAT3 and AKT in the renal proximal tubule epithelial cells. J Am Soc Nephrol 2013; in pressGoogle Scholar
  39. 39.
    Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, et al. In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology 2011;54:252–261PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Feldstein AE, Gores GJ. Apoptosis in alcoholic and nonalcoholic steatohepatitis. Front Biosci 2005;10:3093–3099PubMedCrossRefGoogle Scholar
  41. 41.
    Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE. Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 2013;57:1773–1783PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2014

Authors and Affiliations

  • Mingjiang Xu
    • 1
  • Binxia Chang
    • 1
  • Stephanie Mathews
    • 1
  • Bin Gao
    • 1
    Email author
  1. 1.Laboratory of Liver DiseasesNational Institute on Alcohol Abuse and Alcoholism, National Institutes of Health (NIAAA/NIH)BethesdaUSA

Personalised recommendations