Hepatic Cannabinoid Signaling in the Regulation of Alcohol-Associated Liver Disease

Abstract

Purpose: The endocannabinoid system has emerged as a key regulatory signaling pathway in the pathophysiology of alcohol-associated liver disease (ALD). More than 30 years of research have established different roles of endocannabinoids and their receptors in various aspects of liver diseases, such as steatosis, inflammation, and fibrosis. However, pharmacological applications of the endocannabinoid system for the treatment of ALD have not been successful because of psychoactive side effects, despite some beneficial effects. Thus, a more delicate and detailed elucidation of the mechanism linking the endocannabinoid system and ALD may be of paramount significance in efforts to apply the system to the treatment of ALD.

Search methods: Three electronic databases (PubMed, MEDLINE, and Cochrane Library) were used for literature search from November 1988 to April 2021. Major keywords used for literature searches were "cannabinoid," "cannabinoid receptor," "ALD," "steatosis," and "fibrosis."

Search results: According to the inclusion and exclusion criteria, the authors selected 47 eligible full-text articles out of 2,691 searched initially. Studies in the past 3 decades revealed the opposite effects of cannabinoid receptors CB1R and CB2R on steatosis, inflammation, and fibrosis in ALD.

Discussion and conclusions: This review summarizes the endocannabinoid signaling in the general physiology of the liver, the pathogenesis of ALD, and some of the potential therapeutic implications of cannabinoid-based treatments for ALD.

Keywords: CB1R; CB2R; alcohol; cell communication; endocannabinoid; fatty liver; metabotropic glutamate receptor 5; xCT.

Figure 1

Biosynthesis and degradation pathways of endocannabinoids. Endogenous cannabinoids (endocannabinoids)—arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG)—have distinct pathways of synthesis and degradation in cells. N-arachidonoyl-phosphatidylethanolamine (NAPE) is synthesized from glycerophospholipid and phosphatidylethanolamine by N-acyltransferase (NAT). Upon stimulation, NAPE subsequently gets hydrolyzed by NAPE-specific phospholipase D (NAPE-PLD) to produce AEA. Synthesis of 2-AG begins with the production of sn-1-acyl-2-arachidonoyl-glycerol (DAG) from glycerophospholipid by phospholipase C (PLC), which is then hydrolyzed by diacylglycerol lipase (DAGL) to 2-AG. The synthesized AEA and 2-AG are transported out of the cell by an endocannabinoid membrane transporter (EMT). The released AEA and 2-AG then bind their cannabinoid and noncannabinoid receptors in the neighboring cells to transduce extracellular signals. 2-AG binds both cannabinoid-1 receptor (CB1R) and cannabinoid-2 receptor (CB2R) with similar affinity, whereas AEA has a stronger affinity for CB1R. 2-AG and AEA also bind transient receptor potential vanilloid type-1 (TRPV-1) and orphan G protein-coupled receptors 55 (GPR55) and 119 (GPR119). AEA is hydrolyzed into arachidonic acid (AA) and ethanolamine (EA) by fatty acid amide hydrolase type-1 (FAAH-1) and type-2 (FAAH-2), and N-acylethanolamine-hydrolyzing acid amidase (NAAA), whereas 2-AG is degraded into AA and glycerol by monoacylglycerol lipase (MAGL) and FAAH.

Figure 2

Distribution of cannabinoid receptors in various organs and hepatic cells. Cannabinoid receptors, cannabinoid-1 receptor (CB1R) and cannabinoid-2 receptor (CB2R), are expressed in various central and peripheral organs. CB1R and CB2R are most abundantly expressed in the central nervous system (CNS), where different parts of the CNS express either CB1R or CB2R (blue box). Both CB1R and CB2R are also expressed in peripheral organs including the heart, lung, spleen, pancreas, intestine, bone, muscle, and liver, as well as in the vascular system. Adipose tissues only express CB1R. In the liver, diverse types of cells—including hepatocytes (HEP), cholangiocytes (bile duct [BD] epithelial cells), hepatic stellate cells (HSC), Kupffer cells (KC), and lymphocytes (LYMPH)—differentially express cannabinoid receptors (CB1R and CB2R) and orphan G protein-coupled receptor 55 (GPR55), a noncannabinoid receptor that binds with endocannabinoids 2-AG and AEA (red box, top). Different functions of CB1R and CB2R in the liver are also indicated (red box, bottom).

Figure 3

Cannabinoid signaling in the pathogenesis of alcohol-associated liver disease. Alcohol is mainly metabolized in hepatocytes (HEP) of the liver during which reactive oxygen species (ROS) is generated as a cellular stress response. The generated ROS stimulates and activates a cystine/glutamate antiporter (xCT) for the influx of cystine in exchange for the efflux of glutamate. The excreted glutamate then binds to a metabotropic glutamate receptor 5 (mGluR5) expressed in the neighboring hepatic stellate cells (HSC), inducing the production of 2-arachidonoyl glycerol (2-AG) by diacylglycerol lipase (DAGL). 2-AG produced in the HSC binds to cannabinoid-1 receptors (CB1R) expressed in the plasma membrane of neighboring HEP to induce de novo lipogenesis via the upregulation of sterol regulatory element-binding protein 1c (SREBP1c) and fatty acid synthase (FAS). This forms a bidirectional paracrine loop pathway through which HEP and HSC in close proximity can metabolically regulate each other. Activation of CB1R can also induce β-oxidation of fatty acids in mitochondria, generating mitochondrial ROS (mtROS), which ultimately contributes to the accumulation of fat, or steatosis. Activated CB1R perturbs the excretion of triglyceride (TG) in the form of TG-rich very low-density lipoprotein (VLDL), further contributing to hepatic steatosis. CB1R activation is also known to induce apoptosis of cells. Kupffer cells (KC) normally become activated via the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) stimulation and acquire a pro-inflammatory (M1) phenotype. However, when the CB2R expressed in Kupffer cells are stimulated by ethanol, they obtain an anti-inflammatory (M2) phenotype. Activated Kupffer cells then produce arachidonoyl ethanolamide (AEA), which also binds and activates CB1R in the neighboring HEP.