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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

Abstract

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.

Notes

Acknowledgments

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.

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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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