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.

Evaluation of plasma-free endocannabinoids and their congeners in abstinent cocaine addicts seeking outpatient treatment: impact of psychiatric co-morbidity

“…Further studies have been conducted to determine circulating eCB levels in alcohol users (Mangieri et al . ; Siegmund ; Feuerecker et al . ).…”

Interactions Between Alcohol and the Endocannabinoid System

“…Here, I review progress in our understanding of the role of the ECS both in EtOH‐seeking behavior and in EtOH‐induced organ damage, with a focus on recent advances. For many important earlier studies, the reader is referred to excellent recent reviews of this topic (Gianessi et al, 2019; Henderson‐Redmond et al, 2016; Maccioni et al, 2010; Pava and Woodward, 2012; Siegmund, 2010; Talani and Lovinger, 2015).…”

4-O′-methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice

“…In particular, upregulation of cannabinoid receptors (CB) 1 and 2 in mostly all cronic liver diseases, cirrhosis and related disturbances were convincingly demonstrated, leading to the intriguing therapeutic concept of functional antagonism of these receptors in liver pathophysiology, with CB1 promoting and CB2 protecting from liver damage (5,6) (7). Thus, in CB1 −/− and CB2 -/mice, deletion of CB1 improved hepatic fibrosis and steatosis induced by carbon tetrachloride or high-fat-diet, whereas the lack of CB2 increased collagen deposition, liver fat and inflammation (8,9). In experimental alcoholic models the CB2 agonist JWH-133 showed protective effects, as reflected by improved hepatic fibrosis, steatosis, inflammation and liver regeneration (10)(11)(12).…”