glyceryl-2-arachidonate and Liver-Diseases

2-Arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA) are endocannabinoids that have been implicated in many physiologic disorders, including obesity, metabolic syndromes, hepatic diseases, pain, neurologic disorders, and inflammation. Their immunomodulatory effects are numerous and are not always mediated by cannabinoid receptors, reflecting the presence of an arachidonic acid (AA) molecule in their structure, the latter being the precursor of numerous bioactive lipids that are pro- or anti-inflammatory. 2-AG and AEA can thus serve as a source of AA but can also be metabolized by most eicosanoid biosynthetic enzymes, yielding additional lipids. In this regard, enhancing endocannabinoid levels by using endocannabinoid hydrolysis inhibitors is likely to augment the levels of these lipids that could regulate inflammatory cell functions. This review summarizes the metabolic pathways involved in the biosynthesis and metabolism of AEA and 2-AG, as well as the biologic effects of the 2-AG and AEA lipidomes in the regulation of inflammation.

Topics: Animals; Arachidonic Acids; Dendritic Cells; Endocannabinoids; Glycerides; Humans; Inflammation; Lipid Metabolism; Liver Diseases; Lymphocytes; Metabolic Syndrome; Neurodegenerative Diseases; Obesity; Pain; Phosphatidic Acids; Polyunsaturated Alkamides; Receptors, Cannabinoid

Endocannabinoids are endogenous compounds that bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. They have been found to have many physiological and patho-physiological functions, including mood alteration, control of feeding and appetite, motor and co-ordination activities, analgesia, immune modulation and gut motility. In this review we aim to elucidate current knowledge as to their role in liver physiology and disease.. The major findings published to date concerning endocannabinoids and liver disease are described, and their implications with regard to understanding disease mechanisms, and the development of new treatments is considered.. Recently, endocannabinoids have been implicated in the hemodynamic alterations occurring in cirrhosis. These changes appear to be mediated via specific cannabinoid receptors (CB1) on splanchnic and hepatic vascular endothelium. Plasma levels of endocannabinoids also seem to be elevated in hepatitis, and are involved in apoptosis of hepatocytes by a membrane mechanism not related to a specific receptor. Other studies suggest a beneficial role for cannabinoids in reducing the inflammation of experimental hepatitis. In an animal model of acute hepatic failure, both endocannabinoids and the antagonist to the CB1 receptor have been found to have a beneficial effect on neurological and cognitive function.. Endocannabinoids appear to be involved in several aspects of acute and chronic liver disease, including vascular changes, modulation of inflammatory process and neurological function, Further research may provide new insights into the pathophysiology of liver disease, as well as a basis for novel treatment modalities.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Endocannabinoids; Glycerides; Humans; Liver Diseases; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

In the present study, we examined the changes of F(2)-isoprostanes (non-cyclooxygenase-derived prostanoids), endocannabinoids (2-arachidonylglycerol; 2-AG, arachidoylethanolamide; AEA), and malondialdehyde (MDA: a conventional index of lipid peroxidation) in a porcine warm hepatic ischemia/reperfusion (I/R) model to evaluate the usefulness of each parameter as a marker of lipid peroxidation.. Five female pigs weighing 20 to 22 kg were used in this experiment. Total liver ischemia was achieved by clamping the hepatic pedicle. To prevent splanchnic congestion during occlusion of the portal vein, a portocaval shunt was created with a Dacron graft. After 90 min of ischemia, the liver was reperfused for 120 min. We measured the plasma levels of four markers (F(2)-isoprostanes, 2-AG, AEA, and MDA) from a viewpoint of whether it is useful as a sensitive marker of lipid peroxidation.. Based on statistical analysis using repeated-measures ANOVA, F(2)-isoprostanes demonstrated the most significant changes and were considered to be a highly sensitive marker (P = 0.0001). 2-AG showed less prominent but significant changes (P = 0.0286), followed by MDA (P = 0.0310). However, AEA did not show statistically significant changes over time. The pattern of change in the serum transaminase levels, a classic marker of liver damage, as well as the histologic changes, resembled the profile of F(2)-isoprostanes, 2-AG, and MDA.. F(2)-isoprostanes and 2-AG may be useful as markers of oxidative stress in hepatic I/R injury.

Topics: Alanine Transaminase; Animals; Arachidonic Acids; Aspartate Aminotransferases; Biomarkers; Endocannabinoids; F2-Isoprostanes; Female; Glycerides; Lipid Peroxidation; Liver; Liver Diseases; Liver Function Tests; Malondialdehyde; Reperfusion Injury; Swine

Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication that can follow liver surgery or transplantation. We have investigated the involvement of the endocannabinoid system in hepatic I/R injury using an in vivo mouse model. Here we report that I/R triggers several-fold increases in the hepatic levels of the endocannabinoids anandamide and 2-arachidonoylglycerol, which originate from hepatocytes, Kupffer, and endothelial cells. The I/R-induced increased tissue endocannabinoid levels positively correlate with the degree of hepatic damage and serum TNF-alpha, MIP-1alpha, and MIP-2 levels. Furthermore, a brief exposure of hepatocytes to various oxidants (H2O2 and peroxynitrite) or inflammatory stimuli (endotoxin and TNF-alpha) also increases endocannabinoid levels. Activation of CB2 cannabinoid receptors by JWH133 protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNF-alpha, MIP-1alpha and MIP-2 levels, tissue lipid peroxidation, and expression of adhesion molecule ICAM-1 in vivo. JWH133 also attenuates the TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and the adhesion of human neutrophils to HLSECs in vitro. Consistent with the protective role of CB2 receptor activation, CB2-/- mice develop increased I/R-induced tissue damage and proinflammatory phenotype. These findings suggest that oxidative/nitrosative stress and inflammatory stimuli may trigger endocannabinoid production, and indicate that targeting CB2 cannabinoid receptors may represent a novel protective strategy against I/R injury. We also demonstrate that CB2-/- mice have a normal hemodynamic profile.

Topics: Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Disease Models, Animal; Endocannabinoids; Glycerides; Humans; Inflammation; Liver; Liver Diseases; Mice; Mice, Knockout; Oxidative Stress; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB2; Reperfusion Injury; Up-Regulation