Recent advances in the understanding of the role of the endocannabinoid system in liver diseases

Abstract

Endocannabinoids are ubiquitous signalling molecules that exert their effects through a number of specific cannabinoid receptors. Recent studies have indicated that this endocannabinoid system is involved in the pathophysiological processes associated with both acute and chronic liver diseases as well as in the complications that arise from these diseases such as hepatic encephalopathy and cardiac problems. Targeting this signalling system has been useful in ameliorating some of the symptoms and consequences in experimental models of these liver diseases. This review summarises the recent advances into our knowledge and understanding of endocannabinoids in liver diseases and highlights potential novel therapeutic strategies that may prove useful to treat these diseases.

Figure 1

Biosynthesis and breakdown of the two predominant endocannabinoids, anandamide (AEA) and 2-arachydonoylglycerol (2-AG). The inset shows the chemical structures of AEA and 2-AG. AEA, arachidonoylethanolamine (anandamide); DAGL, diacylglycerol lipase; EMT, endocannabinoid membrane transporter; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAPE, N-acyl-phosphatidylethanolamine; NAPE-PLC, N-acyl-phosphatidylethanolamine-selective phospholipase C; NAPE-PLD, N-acyl-phosphatidylethanolamineselective phospholipase D; NAT, N-acyltransferase; PE, phosphatidylethanolamine; PLC, phospholipase C; TRPV1, transient receptor potential vanilloid type 1. Reproduced from “Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects: AA Izzo and M Camilleri, Gut; 57; 1140–1155, 2008 [68] with permission from BMJ Publishing Group Ltd.

Figure 2

Schematic diagram depicting the effects of cannabinoids and cannabinoid receptor activation of hepatic stellate cell activation and the resulting liver fibrosis; Cb, cannabinoid receptor; COX-2. Cyclooxygenase 2; TGFb, transforming growth factor b.

Figure 3

Schematic diagram of the potential cell signaling mechanisms responsible for the AEA-induced cell death of proliferating cholangiocytes after BDL. Activation of Cb2 by AEA results in increased intracellular ROS accumulation (red asterisks). This, in turn, results in an increased expression and nuclear translocation of TRX1 (but not TRX2) where it interacts with Ref. In addition, increased ROS results in an upregulation of c-Fos and c-Jun expression, which together constitute the AP-1 DNA-binding activity. However, this transcription factor, under oxidized conditions such as that seen here (i.e., in the presence of increased ROS) fails to retain AP-1 transcriptional activity. This apparent dichotomy is resolved by the reducing properties of the TRX1/Ref complex, which restores the AP-1 complex to its reduced form thereby allowing DNA-binding activity and the subsequent transcription of AP-1 target genes that are responsible for the AEA-induced cell death. Reproduced from DeMorrow et al (Am J Physiol Gastrointest Liver Physiol 2008;294:G506–519) [30], with permission from Am Physiol Soc.

Figure 4

A schematic representation of current knowledge into the effects of endocannabinoids in hepatic encephalopathy. 2-AG, 2-arachidonyl glycerol; AMPK, AMP activated protein kinase; Cb, Cannabinoid receptor; THC, tetrahydrocannabinol.

Figure 5

Opposing effects of the endocannabinoids AEA and 2-AG on cholangiocarcinoma growth occurs in an in vivo xenograft model of cholangiocarcinoma. Mz-ChA-1 cells were injected into the flank of athymic mice. After tumors were established, mice were treated with 10 mg/kg/day (ip) AEA, 2-AG or vehicle, three days per week for 28 days and tumor volume assessed. Reprinted from Frampton et al, [57] Experimental cell research, 2010, 316(9); 1465–1478, with permission from Elsevier.