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

Abstract

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.

Figure 1

Role of the endocannabinoid system in the progression of chronic liver diseases: In western countries, prevailing causes of cirrhosis include chronic alcohol consumption, hepatitis C virus and obesity. Liver disease progression show common sequence of events whatever the origin. Studies over the last few years have shown that cannabinoid receptors [cannabinoid receptor 1 (CB₁) and cannabinoid receptor 2 (CB₂)] and their endogenous ligands are highly up-regulated during chronic liver disease and affect multiple common steps, including steatosis, hepatocyte injury and inflammation (steatohepatitis), fibrosis and liver regeneration.