Molecular Medicine

, Volume 17, Issue 11–12, pp 1285–1294 | Cite as

Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

  • Eleonora Patsenker
  • Matthias Stoll
  • Gunda Millonig
  • Abbas Agaimy
  • Till Wissniowski
  • Vreni Schneider
  • Sebastian Mueller
  • Rudolf Brenneisen
  • Helmut K. Seitz
  • Matthias Ocker
  • Felix Stickel
Research Article


The cannabinoid system (CS) is implicated in the regulation of hepatic fibrosis, steatosis and inflammation, with cannabinoid receptors 1 and 2 (CB1 and CB2) being involved in regulation of pro- and antifibrogenic effects. Daily cannabis smoking is an independent risk factor for the progression of fibrosis in chronic hepatitis C and a mediator of experimental alcoholic steatosis. However, the role and function of CS in alcoholic liver fibrosis (ALF) is unknown so far. Thus, human liver samples from patients with alcoholic liver disease (ALD) were collected for analysis of CB1 expression. In vitro, hepatic stellate cells (HSC) underwent treatment with acetaldehyde, H2O2, endo- and exocannabinoids (2-arachidonoylglycerol (2-AG) and Δ9-tetrahydrocannabinol [THC]), and CB1 antagonist SR141716 (rimonabant). In vivo, CB1 knockout (KO) mice received thioacetamide (TAA)/ethanol (EtOH) to induce fibrosis. As a result, in human ALD, CB1 expression was restricted to areas with advanced fibrosis only. In vitro, acetaldehyde, H2O2, as well as 2-AG and THC, alone or in combination with acetaldehyde, induced CB1 mRNA expression, whereas CB1 blockage with SR141716 dose-dependently inhibited HSC proliferation and downregulated mRNA expression of fibrosis-mediated genes PCα1(I), TIMP-1 and MMP-13. This was paralleled by marked cytotoxicity of SR141716 at high doses (5–10 µmol/L). In vivo, CB1 knockout mice showed marked resistance to alcoholic liver fibrosis. In conclusion, CB1 expression is upregulated in human ALF, which is at least in part triggered by acetaldehyde (AA) and oxidative stress. Inhibition of CB1 by SR141716, or via genetic knock-out protects against alcoholic-induced fibrosis in vitro and in vivo.



We are most grateful to Andreas Zimmer from the University of Bonn, Germany, for providing access to the CB1−/− mice. This work was supported by grant 3100 A0 -122114/1 from the Swiss National Science Foundation and by the European Research Advisory Board (ERAB; grant EA 09 20). MO was supported by a grant of the von-Behring-Röntgen Foundation, Marburg, Germany. HKS received funding from the Manfred Lautenschläger Foundation, Heidelberg, Germany.

Supplementary material

10020_2011_17111285_MOESM1_ESM.pdf (453 kb)
Supplementary material, approximately 452 KB.


  1. 1.
    Bataller R, Brenner DA. (2005) Liver fibrosis. J. Clin. Invest. 115:209–18.CrossRefPubMedGoogle Scholar
  2. 2.
    Bataller R, Brenner DA. (2001) Hepatic stellate cells as a target for the treatment of liver fibrosis. Semin. Liver Dis. 21:437–51.CrossRefPubMedGoogle Scholar
  3. 3.
    Parsons CJ, Takashima M, Rippe RA. (2007) Molecular mechanisms of hepatic fibrogenesis. J. Gastroenterol. Hepatol. 22 Suppl 1:S79–84.CrossRefPubMedGoogle Scholar
  4. 4.
    Friedman SL. (2008) Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–69.CrossRefPubMedGoogle Scholar
  5. 5.
    Mallat A, Teixeira-Clerc F, Deveaux V, Lotersztajn S. (2007) Cannabinoid receptors as new targets of antifibrosing strategies during chronic liver diseases. Expert Opin. Ther. Targets 11:403–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Caraceni P, Domenicali M, Bernardi M. (2008) The endocannabinoid system and liver diseases. J. Neuroendocrinol. 20Suppl 1:47–52.CrossRefPubMedGoogle Scholar
  7. 7.
    Parfieniuk A, Flisiak R. (2008) Role of cannabinoids in chronic liver diseases. World J. Gastroenterol. 14:6109–14.CrossRefPubMedGoogle Scholar
  8. 8.
    Siegmund SV, Schwabe RF. (2008) Endocannabinoids and liver disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 294:G357–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Teixeira-Clerc F, et al. (2006) CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat. Med. 12:671–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Julien B, et al. (2005) Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology. 128:742–55.CrossRefPubMedGoogle Scholar
  11. 11.
    Ishida JH, et al. (2008) Influence of cannabis use on severity of hepatitis C disease. Clin. Gastroenterol. Hepatol. 6:69–75.CrossRefPubMedGoogle Scholar
  12. 12.
    Hezode C, et al. (2005) Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology. 42:63–71.CrossRefPubMedGoogle Scholar
  13. 13.
    Hezode C, et al. (2008) Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C. Gastroenterology. 134:432–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Caraceni P, et al. (2009) Circulating and hepatic endocannabinoids and endocannabinoid-related molecules in patients with cirrhosis. Liver Int. 30:816–25.CrossRefPubMedGoogle Scholar
  15. 15.
    Biswas KK, et al. (2003) Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis. Hepatology. 38:1167–77.CrossRefPubMedGoogle Scholar
  16. 16.
    Osei-Hyiaman D, et al. (2005) Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 115:1298–305.CrossRefPubMedGoogle Scholar
  17. 17.
    Siegmund SV, et al. (2006) Fatty acid amide hydrolase determines anandamide-induced cell death in the liver. J. Biol. Chem. 281:10431–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Maccarrone M, Finazzi-Agro A. (2003) The endocannabinoid system, anandamide and the regulation of mammalian cell apoptosis. Cell Death Differ. 10:946–55.CrossRefPubMedGoogle Scholar
  19. 19.
    Siegmund SV, Uchinami H, Osawa Y, Brenner DA, Schwabe RF. (2005) Anandamide induces necrosis in primary hepatic stellate cells. Hepatology. 41:1085–95.CrossRefGoogle Scholar
  20. 20.
    Siegmund SV, et al. (2007) The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J. 21:2798–806.CrossRefPubMedGoogle Scholar
  21. 21.
    Jeong WI, et al. (2008) Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab. 7:227–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Trebicka J, et al. (2011) Role of cannabinoid receptors in alcoholic hepatic injury: steatosis and fibrogenesis are increased in CB2 receptor-deficient mice and decreased in CB1 receptor knockouts. Liver Int. 31:860–70.CrossRefPubMedGoogle Scholar
  23. 23.
    Louvet A, et al. (2011) Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating kupffer cell polarization in mice. Hepatology. doi: 10.1002/hep.24524. [Epub ahead of print].CrossRefPubMedGoogle Scholar
  24. 24.
    Siegmund SV, Haas S, Singer MV (2005) Animal models and their results in gastrointestinal alcohol research. Dig. Dis. 23:181–94.CrossRefPubMedGoogle Scholar
  25. 25.
    Kleiner DE, et al. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 41:1313–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Kornek M, et al. (2006) Combination of systemic thioacetamide (TAA) injections and ethanol feeding accelerates hepatic fibrosis in C3H/He mice and is associated with intrahepatic up regulation of MMP-2, VEGF and ICAM-1. J. Hepatol. 45:370–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Patsenker E, et al. (2008) Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology. 135:660–70.CrossRefPubMedGoogle Scholar
  28. 28.
    Patsenker E, et al. (2009) Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology. 50:1501–11.CrossRefPubMedGoogle Scholar
  29. 29.
    Patsenker E, Popov Y, Wiesner M, Goodman SL, Schuppan D. (2007) Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro. J. Hepatol. 46:878–87.CrossRefPubMedGoogle Scholar
  30. 30.
    Failli P, et al. (1995) The mitogenic effect of platelet-derived growth factor in human hepatic stellate cells requires calcium influx. Am. J. Physiol. 269: C1133–9.Google Scholar
  31. 31.
    Inagaki Y, et al. (1995) Regulation of the alpha 2(I) collagen gene transcription in fat-storing cells derived from a cirrhotic liver. Hepatology. 22:573–9.PubMedGoogle Scholar
  32. 32.
    Rojkind M, et al. (1995) Characterization and functional studies on rat liver fat-storing cell line and freshly isolated hepatocyte coculture system. Am. J. Pathol. 146:1508–20.Google Scholar
  33. 33.
    Pacher P, Gao B. (2008) Endocannabinoids and liver disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases. Am. J. Physiol. Gastrointest. Liver Physiol. 294:G850–4.CrossRefGoogle Scholar
  34. 34.
    Benyon RC, Arthur MJ. (2001) Extracellular matrix degradation and the role of hepatic stellate cells. Semin. Liver Dis. 21:373–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Fallowfield JA, et al. (2007) Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178:5288–95.CrossRefPubMedGoogle Scholar
  36. 36.
    Winwood PJ, et al. (1995) Kupffer cell-derived 95-kd type IV collagenase/gelatinase B: characterization and expression in cultured cells. Hepatology. 22:304–15.PubMedGoogle Scholar
  37. 37.
    Popov Y, et al. Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 298:G323-34.CrossRefPubMedGoogle Scholar
  38. 38.
    Olaso E, et al. (2001) DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J. Clin. Invest. 108:1369–78.CrossRefPubMedGoogle Scholar
  39. 39.
    Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D. (2005) Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J. Hepatol. 43:1045–54.CrossRefPubMedGoogle Scholar
  40. 40.
    Klein TW, et al. (2003) The cannabinoid system and immune modulation. J. Leukoc. Biol. 74:486–96.CrossRefPubMedGoogle Scholar
  41. 41.
    Gary-Bobo M, et al. (2007) Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 46:122–9.CrossRefPubMedGoogle Scholar
  42. 42.
    Chen YH, Wang MF, Liao JW, Chang SP, Hu ML. (2008) Beneficial effects of nicotinamide on alcohol-induced liver injury in senescence-accelerated mice. Biofactors. 34:97–107.CrossRefPubMedGoogle Scholar
  43. 43.
    Brenner DA, Chojkier M. (1987) Acetaldehyde increases collagen gene transcription in cultured human fibroblasts. J. Biol. Chem. 262:17690–5.PubMedGoogle Scholar
  44. 44.
    Eriksson CJ, Sippel HW. (1977) The distribution and metabolism of acetaldehyde in rats during ethanol oxidation-I. The distribution of acetaldehyde in liver, brain, blood and breath. Biochem. Pharmacol. 26:241–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Chen A. (2002) Acetaldehyde stimulates the activation of latent transforming growth factor-beta1 and induces expression of the type II receptor of the cytokine in rat cultured hepatic stellate cells. Biochem. J. 368:683–93.CrossRefPubMedGoogle Scholar
  46. 46.
    Siegmund SV, Dooley S, Brenner DA. (2005) Molecular mechanisms of alcohol-induced hepatic fibrosis. Dig. Dis. 23:264–74.CrossRefPubMedGoogle Scholar
  47. 47.
    Soyka M, et al. (2008) Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial. J. Clin. Psychopharmacol. 28:317–24.CrossRefPubMedGoogle Scholar
  48. 48.
    European Medicines Agency. (2008) The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia [press release]. [cited 2011 Oct 28]. Available from:

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Eleonora Patsenker
    • 1
  • Matthias Stoll
    • 2
    • 6
  • Gunda Millonig
    • 3
  • Abbas Agaimy
    • 4
  • Till Wissniowski
    • 2
  • Vreni Schneider
    • 1
  • Sebastian Mueller
    • 3
  • Rudolf Brenneisen
    • 5
  • Helmut K. Seitz
    • 3
  • Matthias Ocker
    • 2
    • 6
  • Felix Stickel
    • 1
  1. 1.Department of Clinical Pharmacology and Visceral ResearchUniversity of BernBernSwitzerland
  2. 2.Department of MedicineUniversity Hospital ErlangenErlangenGermany
  3. 3.Center of Alcohol Research, Liver Disease and NutritionUniversity of HeidelbergHeidelbergGermany
  4. 4.Department of PathologyUniversity Hospital ErlangenErlangenGermany
  5. 5.Department of Clinical ResearchUniversity of BernBernSwitzerland
  6. 6.Institute for Surgical ResearchPhilipps University MarburgMarburgGermany

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