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CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis

Nature Medicine volume 12, pages 671–676 (2006)Cite this article

Abstract

Hepatic fibrosis, the common response associated with chronic liver diseases, ultimately leads to cirrhosis, a major public health problem worldwide1. We recently showed that activation of hepatic cannabinoid CB2 receptors limits progression of experimental liver fibrosis2. We also found that during the course of chronic hepatitis C, daily cannabis use is an independent predictor of fibrosis progression3. Overall, these results suggest that endocannabinoids may drive both CB2-mediated antifibrogenic effects and CB2-independent profibrogenic effects. Here we investigated whether activation of cannabinoid CB1 receptors (encoded by Cnr1) promotes progression of fibrosis. CB1 receptors were highly induced in human cirrhotic samples and in liver fibrogenic cells. Treatment with the CB1 receptor antagonist SR141716A decreased the wound-healing response to acute liver injury and inhibited progression of fibrosis in three models of chronic liver injury. We saw similar changes in Cnr1−/− mice as compared to wild-type mice. Genetic or pharmacological inactivation of CB1 receptors decreased fibrogenesis by lowering hepatic transforming growth factor (TGF)-β1 and reducing accumulation of fibrogenic cells in the liver after apoptosis and growth inhibition of hepatic myofibroblasts. In conclusion, our study shows that CB1 receptor antagonists hold promise for the treatment of liver fibrosis.

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Figure 1: Hepatic expression of CB1 receptor during chronic liver diseases.
Figure 2: CB1 receptor antagonism decreases accumulation of hepatic myofibroblasts and expression of TGF-β1 in an acute model of matrix remodelling.
Figure 3: CB1 receptor antagonism reduces fibrosis associated with chronic liver injury.
Figure 4: Genetic or pharmacological inactivation of CB1 receptors reduces accumulation of mouse hepatic myofibroblasts in vitro and in vivo: the effect on proliferation and apoptosis.

References

  1. Lotersztajn, S., Julien, B., Teixeira-Clerc, F., Grenard, P. & Mallat, A. Hepatic fibrosis: molecular mechanisms and drug targets. Annu. Rev. Pharmacol. Toxicol. 45, 605–628 (2005).

    CAS  Article  Google Scholar 

  2. Julien, B. et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128, 742–755 (2005).

    CAS  Article  Google Scholar 

  3. Hezode, C. et al. Daily cannabis smoking as a risk factor for fibrosis progression in chronic hepatitis C. Hepatology 42, 63–71 (2005).

    CAS  Article  Google Scholar 

  4. Pertwee, R.G. Pharmacology of cannabinoid receptor ligands. Curr. Med. Chem. 6, 635–664 (1999).

    CAS  PubMed  Google Scholar 

  5. Di Marzo, V., Bifulco, M. & De Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nat. Rev. Drug Discov. 3, 771–784 (2004).

    CAS  Article  Google Scholar 

  6. Piomelli, D., Giuffrida, A., Calignano, A. & Rodriguez de Fonseca, F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21, 218–224 (2000).

    CAS  Article  Google Scholar 

  7. Guzman, M. Cannabinoids: potential anticancer agents. Nat. Rev. Cancer 3, 745–755 (2003).

    CAS  Article  Google Scholar 

  8. Mallat, A. & Lotersztajn, S. Endocannabinoids as novel mediators of liver diseases. J. Endocrinol. Invest. (in the press).

  9. Bilkei-Gorzo, A. et al. Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc. Natl. Acad. Sci. USA 102, 15670–15675 (2005).

    CAS  Article  Google Scholar 

  10. Wang, L., Liu, J., Harvey-White, J., Zimmer, A. & Kunos, G. Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc. Natl. Acad. Sci. USA 100, 1393–1398 (2003).

    CAS  Article  Google Scholar 

  11. Cota, D. et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423–431 (2003).

    CAS  Article  Google Scholar 

  12. Li, L. et al. 15-Deoxy-delta 12,14-prostaglandin j2 induces apoptosis of human hepatic myofibroblasts. a pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors. J. Biol. Chem. 276, 38152–38158 (2001).

    CAS  PubMed  Google Scholar 

  13. Davaille, J., Li, L., Mallat, A. & Lotersztajn, S. Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts. J. Biol. Chem. 277, 37323–37330 (2002).

    CAS  Article  Google Scholar 

  14. Davaille, J. et al. Antiproliferative properties of sphingosine 1-phosphate in human hepatic myofibroblasts. A cyclooxygenase-2 mediated pathway. J. Biol. Chem. 275, 34628–34633 (2000).

    CAS  Article  Google Scholar 

  15. Tao, J. et al. Biological effects of C-type natriuretic peptide in human myofibroblastic hepatic stellate cells. J. Biol. Chem. 274, 23761–23769 (1999).

    CAS  Article  Google Scholar 

  16. Batkai, S. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat. Med. 7, 827–832 (2001).

    CAS  Article  Google Scholar 

  17. Ros, J. et al. Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat. Gastroenterology 122, 85–93 (2002).

    CAS  Article  Google Scholar 

  18. Siegmund, S.V., Uchinami, H., Osawa, Y., Brenner, D.A. & Schwabe, R.F. Anandamide induces necrosis in primary hepatic stellate cells. Hepatology 41, 1085–1095 (2005).

    CAS  Article  Google Scholar 

  19. Milligan, G. Constitutive activity and inverse agonists of G protein-coupled receptors: a current perspective. Mol. Pharmacol. 64, 1271–1276 (2003).

    CAS  Article  Google Scholar 

  20. Bouaboula, M. et al. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J. Biol. Chem. 272, 22330–22339 (1997).

    CAS  Article  Google Scholar 

  21. Rinaldi Carmona, M. et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998).

    CAS  PubMed  Google Scholar 

  22. Van Gaal, L.F., Rissanen, A.M., Scheen, A.J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005).

    CAS  Article  Google Scholar 

  23. Despres, J.P., Golay, A. & Sjostrom, L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 353, 2121–2134 (2005).

    CAS  Article  Google Scholar 

  24. Biecker, E., Sagesser, H. & Reichen, J. Vasodilator mRNA levels are increased in the livers of portal hypertensive NO-synthase 3-deficient mice. Eur. J. Clin. Invest. 34, 283–289 (2004).

    CAS  Article  Google Scholar 

  25. Osei Hyiaman, D. et al. Endocannabinoid activation at hepatic CB(1) receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 115, 1298–1305 (2005).

    CAS  Article  Google Scholar 

  26. Rinaldi Carmona, M. et al. Characterization and distribution of binding sites for [3H]-SR141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain. Life Sci. 58, 1239–1247 (1996).

    CAS  Article  Google Scholar 

  27. Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).

    CAS  Article  Google Scholar 

  28. Li, X., Benjamin, I.S. & Alexander, B. Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality. J. Hepatol. 36, 488–493 (2002).

    Article  Google Scholar 

  29. Li, L. et al. Heme oxygenase-1 is an antifibrogenic protein in human hepatic myofibroblasts. Gastroenterology 125, 460–469 (2003).

    CAS  Article  Google Scholar 

  30. Vrochides, D., Papanikolaou, V., Pertoft, H., Antoniades, A.A. & Heldin, P. Biosynthesis and degradation of hyaluronan by nonparenchymal liver cells during liver regeneration. Hepatology 23, 1650–1655 (1996).

    CAS  Article  Google Scholar 

  31. Li, L. et al. Molecular mechanisms regulating the antifibrogenic protein heme oxygenase-1 in human hepatic myofi broblasts. J. Hepatol. 41, 407–413 (2004).

    CAS  Article  Google Scholar 

  32. Pfaffl, M.W., Horgan, G.W. & Dempfle, L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 30, e36 (2002).

    Article  Google Scholar 

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Acknowledgements

P.G. was supported by INSERM, B.J. by a fellowship from the Ministère de la Recherche et de la Technologie and L.L. by a fellowship from Fondation pour la Recherche Médicale. This work was supported by the INSERM, the Université Paris-Val-de-Marne, and by grants from Sanofi-Aventis, the Association pour la Recherche sur le Cancer, the Ligue départementale du Val de Marne de la Recherche contre le Cancer and of the Agence Nationale de la Recherche (to S.L.). We thank F. Pecker for guidance, G. Guellaen for discussions and support, J. Hanoune and H. Gilgenkrantz for suggestions and C. Pavoine for critical reading of the manuscript. We are grateful to S. Adubeiro for her help during in vivo experiments, to D. Derai (Département de Pathologie, Hôpital Henri Mondor) for technical assistance in histology experiments, to A. Laurent (Service de Chirurgie Digestive, Hôpital Henri Mondor) and V. Fauveau (Institut Cochin, Paris) for their help in surgical setting of bile duct ligation experiments, and to F. Lafdil for providing hepatic stellate cells.

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Author notes

  1. Fatima Teixeira-Clerc, Boris Julien and Pascale Grenard: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, Unité 581, Hôpital Henri Mondor Créteil, F-9400, France

    Fatima Teixeira-Clerc, Boris Julien, Pascale Grenard, Jeanne Tran Van Nhieu, Vanessa Deveaux, Liying Li, Valérie Serriere-Lanneau, Ariane Mallat & Sophie Lotersztajn

  2. Université Paris 12, Faculté de Médecine, Créteil, F-94000, France

    Fatima Teixeira-Clerc, Boris Julien, Pascale Grenard, Jeanne Tran Van Nhieu, Vanessa Deveaux, Liying Li, Valérie Serriere-Lanneau, Ariane Mallat & Sophie Lotersztajn

  3. AP-HP, Groupe Hospitalier Henri Mondor-Albert Chenevier, Service d'Hépatologie et de Gastroentérologie, Créteil, F-94000, France

    Ariane Mallat & Sophie Lotersztajn

  4. Département de Pathologie, AP-HP, Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, F-94000, France

    Jeanne Tran Van Nhieu

  5. IRIBHN, Université Libre de Bruxelles, Bruxelles, Belgium

    Catherine Ledent

Authors
  1. Fatima Teixeira-Clerc
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  2. Boris Julien
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  10. Sophie Lotersztajn
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Contributions

F.T.-C., B.J., P.G. & J.T.V.N. designed the study; collected, analyzed and interpreted data; and wrote the manuscript. V.D., L.L., V.S.-L. collected and interpreted data. C.L. conceptualized the study and contributed knockout mice. A.M. conceptualized and designed the study, interpreted data and revised the manuscript. S.L. conceptualized and designed the study and wrote and revised the manuscript.

Corresponding author

Correspondence to Sophie Lotersztajn.

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Competing interests

An application for an international patent (Use of antagonists of the CB1 receptor for the manufacture of a composition useful for the treatment of hepatic diseases; WO 2005/084652) is connected to this work.

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Teixeira-Clerc, F., Julien, B., Grenard, P. et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 12, 671–676 (2006). https://doi.org/10.1038/nm1421

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