Title:The Effect of CB1 Antagonism on Hepatic Oxidative/Nitrosative Stress and Inflammation in Nonalcoholic Fatty Liver Disease
VOLUME: 28 ISSUE: 1
Author(s):Bojan Jorgačević, Danijela Vučević, Janko Samardžić, Dušan Mladenović, Milena Vesković, Dušan Vukićević, Rada Ješić and Tatjana Radosavljević*
Affiliation:Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Digestive Diseases, Clinical Centre of Serbia, 11000 Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, 11000 Belgrade
Keywords:NAFLD, endocannabinoids, CB receptors, CB1 antagonism, oxidative/nitrosative stress, inflammation,
endocannabinoid system (ES).
Abstract:Dysfunction of the endocannabinoid system (ES) has been identified in nonalcoholic fatty
liver disease (NAFLD) and associated metabolic disorders. Cannabinoid receptor type 1 (CB1) expression
is largely dependent on nutritional status. Thus, individuals suffering from NAFLD and
metabolic syndrome (MS) have a significant increase in ES activity. Furthermore, oxidative/
nitrosative stress and inflammatory process modulation in the liver are highly influenced by the
ES. Numerous experimental studies indicate that oxidative and nitrosative stress in the liver is associated
with steatosis and portal inflammation during NAFLD. On the other hand, inflammation itself
may also contribute to reactive oxygen species (ROS) production due to Kupffer cell activation and
increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The pathways by
which endocannabinoids and their lipid-related mediators modulate oxidative stress and lipid peroxidation
represent a significant area of research that could yield novel pharmaceutical strategies for the
treatment of NAFLD. Cumulative evidence suggested that the ES, particularly CB1 receptors, may
also play a role in inflammation and disease progression toward steatohepatitis. Pharmacological
inactivation of CB1 receptors in NAFLD exerts multiple beneficial effects, particularly due to the
attenuation of hepatic oxidative/nitrosative stress parameters and significant reduction of proinflammatory
cytokine production. However, further investigations regarding precise mechanisms by
which CB1 blockade influences the reduction of hepatic oxidative/nitrosative stress and inflammation
are required before moving toward the clinical phase of the investigation.
