The Peripheral CB Receptor Antagonist JD5037 Attenuates Liver Fibrosis Via a CB Receptor/β-arrestin1/Akt Pathway

Background And Purpose: Liver fibrosis is a serious cause of morbidity and mortality worldwide and has no adequate treatment. Accumulating evidence suggests that cannabinoid CB receptors regulate a variety of physiological and pathological processes in the liver, and blockage of CB 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 CB receptors and a peripheral CB receptor antagonist JD5037 in liver fibrogenesis.

Experimental Approach: Liver samples from both humans and mouse models were investigated. The peripheral CB receptor antagonist JD5037, β-arr1 wild type (β-arr1-WT) and β-arr1 knockout (β-arr1-KO) littermate models, and primary hepatic stellate cells (HSCs) were also used. The mechanisms underlying CB receptor-regulated HSCs activation in fibrosis and the therapeutic potential of JD5037 were further analysed.

Key Results: CB 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 β-arrestin1 and Akt signalling, while blockage of CB receptors with JD5037 attenuated CB receptor-regulated HSCs activation and liver fibrosis by suppressing β-arrestin1/Akt signalling.

Conclusions And Implications: CB receptors promote the activation of HSCs and liver fibrosis via the β-arrestin1/Akt signalling pathway. The peripheral CB 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.