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

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.

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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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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.

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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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