The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings.

Chronic liver diseases represent a major health problem due to cirrhosis and its complications. During the last decade, endocannabinoids and their receptors have emerged as major regulators of several pathophysiological aspects associated with chronic liver disease progression. Hence, hepatic cannabinoid receptor 2 (CB(2)) receptors display beneficial effects on alcoholic fatty liver, hepatic inflammation, liver injury, regeneration and fibrosis. Cannabinoid receptor 1 (CB(1)) receptors have been implicated in the pathogenesis of several lesions such as alcoholic and metabolic steatosis, liver fibrogenesis, or circulatory failure associated with cirrhosis. Although the development of CB(1) antagonists has recently been suspended due to the high incidence of central side effects, preliminary preclinical data obtained with peripherally restricted CB(1) antagonists give real hopes in the development of active CB(1) molecules devoid of central adverse effects. CB(2) -selective molecules may also offer novel perspectives for the treatment of liver diseases, and their clinical development is clearly awaited. Whether combined treatment with a peripherally restricted CB(1) antagonist and a CB(2) agonist might result in an increased therapeutic potential will warrant further investigation.

[The endocannabinoid system as a novel target for the treatment of liver fibrosis]. / Le système endocannabinoïde, une nouvelle cible pour le traitement de la fibrose hépatique.

The cannabinoid system comprises specific G protein-coupled receptors (CB1 and CB2), exogenous (marijuana-derived cannabinoids) and endogenous (endocannabinoids) ligands, and a machinery dedicated to endocannabinoid synthesis and degradation. Studies over two decades have extensively documented the crucial role of the cannabinoid system in the regulation of a variety of pathophysiological conditions. However, its role in liver pathology has only been recently unravelled, probably given the low expression of CB1 and CB2 in the normal liver. We have recently demonstrated that CB1 and CB2 receptors display opposite effects in the regulation of liver fibrogenesis during chronic liver injury. Indeed, both receptors are up-regulated in the liver of cirrhotic patients, and expressed in liver fibrogenic cells. Moreover, CB1 receptors are profibrogenic and accordingly, the CB1 antagonist rimonabant reduces fibrosis progression in three experimental models. In keeping with these results, daily cannabis smoking is a risk factor for fibrosis progression in patients with chronic hepatitis C. In contrast, CB2 display antifibrogenic effects, by a mechanism involving reduction of liver fibrogenic cell accumulation. These results may offer new perspectives for the treatment of liver fibrosis, combining CB2 agonist and CB1 antagonist therapy.

CB2 receptors as new therapeutic targets for liver diseases.

Cannabinoid type-1 (CB1) and type-2 (CB2) receptors belong to the family of G protein-coupled receptors and mediate biological effects of phyto-derived and endogenous cannabinoids. Whereas functions of CB1 receptor have been extensively studied, the CB2 receptor has emerged over the last few years as a critical player in regulation of inflammation, pain, atherosclerosis and osteoporosis. Therefore, although still at a preclinical stage, the development of selective CB2 molecules has gained of interest as new targets in drug discovery. Recent data have unravelled a key role of CB2 receptors during chronic and acute liver injury, including fibrogenesis associated to chronic liver diseases, ischaemia-reperfusion-induced liver injury, and hepatic encephalopathy associated to acute liver failure. This review summarizes the latest advances on the recently identified role of CB2 receptors in the pathophysiology of liver diseases.