Abstract
There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1 promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.
Highlights
The endocannabinoid system (ECS) is a complex physiological system that affects metabolic pathways in the brain and in peripheral organs [1]
Anandamide is a ligand for the cannabinoid receptors (CBRs) type 1 and 2 (CB1, CB2), it is functionally selective for the Cannabinoid receptor type 1 (CB1) and can interact with non-classic CBRs such as the transient receptor potential vanilloid type 1 (TRPV1) receptor [7] or the nuclear receptors peroxisome proliferation-activated receptor (PPAR)α and PPARγ at high micromolar concentrations [8,9]. 2-AG is a ligand for the CB1 and CB2 receptors und is generally produced from the hydrolysis of 2-arachidonate-containing diacylglycerols
AEA synthesis is under the control of a selective calcium-dependent phospholipase D namely N-arachidonoyl-phosphatidylethanolamine-phospholipase D (NAPE-PLD) whereas the fatty-acid amide hydrolase (FAAH) catalyzes the hydrolysis of anandamide, and to a certain extent 2-AG. 2-AG is formed by two diacylglycerol lipases α and β (DAGLα and β) and hydrolyzed by the monoacylglycerol lipase (MAGL)
Summary
The endocannabinoid system (ECS) is a complex physiological system that affects metabolic pathways in the brain and in peripheral organs [1]. The ECS comprises cannabinoid receptors (CBRs), their endogenous ligands, termed endocannabinoids, and the enzymes involved in the endocannabinoid synthesis and degradation [2,3,4,5]. The first-discovered and best-studied endocannabinoids are anandamide (N-arachidonoyl-ethanolamine, AEA) and 2-arachidonoylglycerol (2-AG). Anandamide is a ligand for the CBRs type 1 and 2 (CB1, CB2), it is functionally selective for the CB1 and can interact with non-classic CBRs such as the transient receptor potential vanilloid type 1 (TRPV1) receptor [7] or the nuclear receptors peroxisome proliferation-activated receptor (PPAR)α and PPARγ at high micromolar concentrations [8,9]. 2-AG is formed by two diacylglycerol lipases α and β (DAGLα and β) and hydrolyzed by the monoacylglycerol lipase (MAGL) Another way to degrade AEA and 2-AG involve oxidation via cyclooxygenase-2 (COX-2) [10,11,12]. Besides the classical CB1 and CB2 receptors, other deorphanized GPCRs such as GPR3, GPR6, GPR18, GPR55, and GPR119 and non-cannabinoid receptors, like the TRPV1, or the peroxisome proliferator-activated receptors (PPARs), are suggested as part of the endocannabinoid system [5,17]
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