Effects of Anandamide on Proliferation and Activation of Hepatic Stellate Cells Through Cannabinoid‐2 Receptors

Abstract

Recent studies have indicated that endogenous endocannabinoids (ECB) are importantly involved in the development of liver cirrhosis. However, the mechanisms mediating the actions of these ECB are still poorly understood. The present study tested the hypothesis that anandamide (AEA) inhibits activation and proliferation of hepatic stellate cells (HSCs) to prevent liver fibrosis via cannabinoid‐2 (CB2) receptors. Using immunocytochemistry and Western blot analysis, we found that both cannabinoid‐1 (CB1) and CB2 receptors were detectable in cultured HSCs with a higher level of CB2 than CB1. When HSCs were stimulated by PDGF, the expression of CB2 receptors was significantly enhanced. By flow cytometry and MTT (methyl thiazolyl tetrazolium) detection, PDGF was found to markedly stimulate proliferation of HSCs, which was inhibited by AEA dose‐dependently. However, this action of AEA was not associated with increased apoptosis or necrosis, and CB2 receptors were not involved. We also found that PDGF‐induced increase in various factors related to activation of HSCs such as alpha‐SMA, TGF‐β, α1 (I) collagen, and TIMP‐1 was substantially suppressed by AEA and that CB2 antagonist AM630 reversed this suppressor action of AEA. These results suggest that AEA may inhibit proliferation and activation of HSCs and CB2 receptors importantly mediate AEA‐induced inhibitory action on activation of these HSCs. This CB2 receptor‐mediated action on HSCs could be a therapeutic target against liver fibrosis. (Supported by National Nature Science Foundation of China 30571627)