Introduction to Endocannabinoid System and Cannabinoids:
The endocannabinoid system, consisting of cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, has recently emerged as an ubiquitous system with key functions in a variety of physiological settings. Identification of the system was initiated two decades ago with the characterization of two G protein-coupled receptors, CB1 and CB2 that show high affinity for Δ9-tetrahydrocannabinol, the main psychoactive constituent of Cannabis sativa. CB1 receptor drives the psychoactive properties of marijuana, and as such is highly expressed in the central nervous system, albeit also present and functional in a wide range of cells and tissues, particularly in those regulating energy balance . In contrast, CB2 receptor displays a more restricted distribution, predominating in immune cells, and has been identified as a major mediator of anti-inflammatory reactions . In addition to phytocannabinoids, CB receptors bind to endogenous lipidic ligands, known as endocannabinoids, among which arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) are the most thoroughly studied. Anandamide exhibits higher affinity for CB1 over CB2 receptors, and 2-AG binds to CB1 and CB2 with similar affinities. Endocannabinoid synthesis occurs on demand from distinct cell membrane phopholipid precursors and predominantly results in paracrine effects. Clearance of anandamide follows cellular uptake by a specific transporter, prior to catabolism by fatty acid amide hydrolase (FAAH), whereas 2-AG is catabolized by monoacyglycerol lipase (MAGL)
The Research done:
Over the last decade, the endocannabinoid system has emerged as a pivotal mediator of acute and chronic liver injury, with the description of the role of CB1 and CB2 receptors and their endogenous lipidic ligands in various aspects of liver pathophysiology.
A large number of studies have demonstrated that CB1 receptor antagonists represent an important therapeutic target, owing to beneficial effects on lipid metabolism and in light of its antifibrogenic properties. Unfortunately, the brain-penetrant CB1 antagonist rimonabant, initially approved for the management of overweight and related cardiometabolic risks, was withdrawn because of an alarming rate of mood adverse effects.
However, the efficacy of peripherally-restricted CB1 antagonists with limited brain penetrance has now been validated in preclinical models of NAFLD, and beneficial effects on “liver” fibrosis and its complications are anticipated.
Overwhelming evidence supports the therapeutic potential of peripherally-restricted CB1 antagonists and CB2 agonists in the management of chronic liver diseases. A major interest of this approach resides in the multiple levels of action of these therapeutic strategies on various steps of chronic liver disease progression. Exciting therapeutic developments are now anticipated from the development of the second generation of neutral and inverse peripherally-restricted CB1 antagonists that show promising effects in preclinical studies.
However, long-term studies are required to confirm the absence of central effects of these new molecules in both experimental models and humans. Based on the promising protective effects of CB2 receptor agonists on various steps of acute and chronic liver disease progression, the development of stable CB2 agonists is also eagerly awaited. Whether the potential of CB2 and CB1-based therapeutics can be turned to reality will be the challenge of the next few years.
Cellular targets of CB1-mediated effects during liver injury. CB1 receptors expressed in hepatocytes and hepatic myofibroblasts contribute to high fat diet and alcohol-induced steatosis, liver regeneration, and fibrogenesis. Steatogenic properties of CB1 result from hepatocyte activation of lipogenesis, reduction of fatty acid oxidation, and decreased release of TG-rich VLDL, combined to CB1-dependent release of free fatty acids from the adipose tissue. While anandamide binding to CB1 receptors drives metabolic steatois, 2-AG is the endogenous ligand promoting alcoholic steatosis. CB1 also activates hepatocyte proliferation and promotes fibrogenesis by enhancing hepatic myofibroblast survival.
Hepatic cellular targets of CB2-mediated protective effects. CB2 receptors expressed in immune cells (Kupffer cells, Th17 lymphocytes) and hepatic myofibroblasts display anti-inflammatory properties and protect against alcohol-induced steatosis, hepatocyte apoptosis, and fibrogenesis. Antifibrogenic properties result from (i) direct CB2-mediated effects on hepatic myofibroblasts and (ii) indirect hepatoprotective effects on hepatocytes, anti-inflammatory properties on Kupffer cell and downregulation of the production of the profibrogenic cytokine IL17 by Th17 lymphocytes.