Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

The cannabinoid system (CS) is implicated in the regulation of hepatic fibrosis, steatosis and inflammation, with cannabinoid receptors 1 and 2 (CB1 and CB2) being involved in regulation of pro- and antifibrogenic effects. Daily cannabis smoking is an independent risk factor for the progression of fibrosis in chronic hepatitis C and a mediator of experimental alcoholic steatosis. However, the role and function of CS in alcoholic liver fibrosis (ALE) is unknown so far. Thus, human liver samples from patients with alcoholic liver disease (ALD) were collected for analysis of GB? expression. In vitro, hepatic stellate cells (HSC) underwent treatment with acetaldehyde, H2O2, endo- and exocannabinoids (2-arachidonoylglycerol (2-AG) and Delta 9-tetrahydrocannabinol (THC)), and CB1 antagonist SR141716 (rimonabant). In viva CB1 knockout (KO) mice received thioacetamide (TAA)/ethanol (EtOH) to induce fibrosis. As a result, in human ALD, CBI expression was restricted to areas with advanced fibrosis only. In vitro, acetaldehyde, H2O2, as well as 2-AG and THC, alone or in combination with acetaldehyde, induced CB) mRNA expression, whereas CB1 blockage with SR141716 dose-dependently inhibited HSC proliferation and downregulated mRNA expression of fibrosis-mediated genes PC alpha 1(I), TIMP-1 and MMP-13. This was paralleled by marked cytotoxicity of SR141716 at high doses (5-10 mu mol/L). In vivo, CB1 knockout mice showed marked resistance to alcoholic liver fibrosis. In conclusion, CBI expression is upregulated in human ALE, which is at least in part triggered by acetaldehyde (AA) and oxidative stress. Inhibition of CB1 by SR141716, or via genetic knock-out protects against alcoholic-induced fibrosis in vitro and in vivo. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00149