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.