Steatohepatitis/Metabolic Liver Disease
Article first published online: 30 JAN 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 3, pages 790–799, March 2012
How to Cite
Jourdan, T., Demizieux, L., Gresti, J., Djaouti, L., Gaba, L., Vergès, B. and Degrace, P. (2012), Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: Evidence from cultured explants. Hepatology, 55: 790–799. doi: 10.1002/hep.24733
Potential conflict of interest: Nothing to report.
This work was supported by grants from Sanofi-Aventis and the Région Bourgogne.
- Issue published online: 23 FEB 2012
- Article first published online: 30 JAN 2012
- Accepted manuscript online: 10 OCT 2011 11:04AM EST
- Manuscript Accepted: 26 SEP 2011
- Manuscript Received: 16 DEC 2010
It is well established that inactivation of the central endocannabinoid system (ECS) through antagonism of cannabinoid receptor 1 (CB1R) reduces food intake and improves several pathological features associated with obesity, such as dyslipidemia and liver steatosis. Nevertheless, recent data indicate that inactivation of peripheral CB1R could also be directly involved in the control of lipid metabolism independently of central CB1R. To further investigate this notion, we tested the direct effect of the specific CB1R antagonist, SR141716, on hepatic carbohydrate and lipid metabolism using cultured liver slices. CB1R messenger RNA expression was strongly decreased by SR141716, whereas it was increased by the CB1R agonist, arachidonic acid N-hydroxyethylamide (AEA), indicating the effectiveness of treatments in modulating ECS activity in liver explants both from lean or ob/ob mice. The measurement of O2 consumption revealed that SR141716 increased carbohydrate or fatty acid utilization, according to the cellular hormonal environment. In line with this, SR141716 stimulated ß-oxidation activity, and the role of CB1R in regulating this pathway was particularly emphasized when ECS was hyperactivated by AEA and in ob/ob tissue. SR141716 also improved carbohydrate and lipid metabolism, blunting the AEA-induced increase in gene expression of proteins related to lipogenesis. In addition, we showed that SR141716 induced cholesterol de novo synthesis and high-density lipoprotein uptake, revealing a relationship between CB1R and cholesterol metabolism. Conclusion: These data suggest that blocking hepatic CB1R improves both carbohydrate and lipid metabolism and confirm that peripheral CB1R should be considered as a promising target to reduce cardiometabolic risk in obesity. (HEPATOLOGY 2011)