Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis

Abstract

Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology—both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.

Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System

“…Given the changes in the hepatic endocannabinoid system associated with LPS/GalN-induced liver injury, and data demonstrating beneficial effects of CB1 antagonism and CB2 receptor agonism in several models of liver disease [ 20 , 27 ], the effects of modulating these receptors on ALI in SD and WKY rats was examined. Two-way ANOVA revealed a significant effect of strain (F 1,46 = 75.47 p < 0.001), treatment (F 3,46 = 7.36 p < 0.001) and strain × treatment interaction (F 3,46 = 3.56 p = 0.021) on the histological score.…”

“…The endocannabinoid system plays a key role in mediation and the modulation of innate immune and hepatic function [ 20 , 21 , 27 , 34 ]. WKY rats exhibit alteration in key components of the endocannabinoid system within discrete brain regions [ 35 , 36 , 37 ] and cannabidiol has been demonstrated to attenuate depressive-like behaviour in this rat strain [ 38 , 39 ].…”

“…A wealth of data has indicated that CB 1 receptor activation is a key mediator in the exacerbation of several liver pathologies and CB 2 receptor activation results in anti-inflammatory and antifibrogenic effects in several models [ 20 , 25 , 27 ]. In an attempt to further elucidate the role of CB 1 and CB 2 receptors in ALI in the current model, the effect of acute systemic administration of CB 1 antagonist and CB 2 agonist on the development of hepatic inflammation and ALI in SD and WKY rats was examined.…”

“…Composed of the G-protein coupled receptors, cannabinoid receptor 1 and 2 (CB 1 and CB 2 ), endogenous cannabinoid ligands including N -arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) and the enzymes responsible for their synthesis and degradation; this system is expressed throughout cells and tissues in the body. In the liver, endocannabinoids, notably AEA and 2-AG, have also been identified as regulators of hepatic haemodynamics [ 17 ], lipid metabolism and fibrogenesis (for review see [ 18 , 19 , 20 , 21 ]). Furthermore, the endocannabinoid system is an important modulator of immune function and TLR4-mediated inflammation [ 22 ].…”

Special Issue on “Cellular and Molecular Mechanisms Underlying the Pathogenesis of Hepatic Fibrosis”

“…The review of Melgar-Lesmes and colleagues summarizes the recent advances in understanding pathophysiologically relevant roles and their potential clinical relevance of both systems. Interestingly, the endocannabinoid and apelin pathways have marked dissimilarities and collaborate with each other in hepatic fibrogenesis [27].…”