title: Role of the endocannabinoid system in alcoholic liver disease.
abstract: Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Alcoholic liver disease (ALD) is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of noxious ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Recent studies suggest that the endocannabinoid system is a signaling system that also plays an important role in the pathogenesis of ALD. A study comparing chronic alcohol administration in cannabinoid receptor (CB) 1 or CB2 knockout versus wild-type mice revealed that CB1 signaling aggravated hepatic steatosis and fibrogenesis whereas CB2 protected the liver from ALD. These data suggested a protective role of CB2 (in contrast to CB1) in ALD. Similar results were found in global or hepatocyte-specific CB1 knockout mice that were resistant to ethanol-induced steatosis. Moreover, ethanol feeding upregulated the endocannabinoid 2-arachidonoyl glycerol and its biosynthetic enzyme diacylglycerol lipase-β selectively in hepatic stellate cells and subsequently increased expression of CB1 receptors in hepatocytes of wild-type mice leading to CB1-dependent hepatic steatosis by activation of lipogenic pathways. This ethanol-induced upregulation of CB1 receptors was partly dependent on the ethanol metabolite acetaldehyde. Thus, the hepatic endocannabinoid system offers emerging options for therapeutic exploitation not only for liver disease in general, but also for ALD.
authors.affiliation: Medical Department I, University of Bonn, Bonn, Germany. soeren.siegmund@ukb.uni-bonn.de
authors.forename: S V
authors.initials: SV
authors.lastname: Siegmund
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D063388:Endocannabinoids; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids