| First Author | Tan S | Year | 2020 |
| Journal | Br J Pharmacol | Volume | 177 |
| Issue | 12 | Pages | 2830-2847 |
| PubMed ID | 32017042 | Mgi Jnum | J:352975 |
| Mgi Id | MGI:6727562 | Doi | 10.1111/bph.15010 |
| Citation | Tan S, et al. (2020) The peripheral CB1 receptor antagonist JD5037 attenuates liver fibrosis via a CB1 receptor/beta-arrestin1/Akt pathway. Br J Pharmacol 177(12):2830-2847 |
| abstractText | BACKGROUND AND PURPOSE: Liver fibrosis is a serious cause of morbidity and mortality worldwide and has no adequate treatment. Accumulating evidence suggests that cannabinoid CB1 receptors regulate a variety of physiological and pathological processes in the liver, and blockage of CB1 receptor signalling shows promise as a new therapy for several liver diseases. The aim of this study was to investigate the potential therapeutic effects of CB1 receptors and a peripheral CB1 receptor antagonist JD5037 in liver fibrogenesis. EXPERIMENTAL APPROACH: Liver samples from both humans and mouse models were investigated. The peripheral CB1 receptor antagonist JD5037, beta-arr1 wild type (beta-arr1-WT) and beta-arr1 knockout (beta-arr1-KO) littermate models, and primary hepatic stellate cells (HSCs) were also used. The mechanisms underlying CB1 receptor-regulated HSCs activation in fibrosis and the therapeutic potential of JD5037 were further analysed. KEY RESULTS: CB1 receptors were induced in samples from patients with liver fibrosis and from mouse models. These receptors promoted activation of HSCs in liver fibrosis via recruiting beta-arrestin1 and Akt signalling, while blockage of CB1 receptors with JD5037 attenuated CB1 receptor-regulated HSCs activation and liver fibrosis by suppressing beta-arrestin1/Akt signalling. CONCLUSIONS AND IMPLICATIONS: CB1 receptors promote the activation of HSCs and liver fibrosis via the beta-arrestin1/Akt signalling pathway. The peripheral CB1 receptor antagonist JD5037 blocked this pathway, the activation of HSCs and liver fibrosis. This compound and the associated pathway may be a novel approach to the treatment of liver fibrosis. |
