Protective effect of rimonabant, a canabinoid receptor 1 antagonist, on nonalcoholic fatty liver disease in a rat model through modulation of the hepatic expression of activin A and follistatin

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver morbidity and mortality, and there is still no proven effective therapy. The endocannabinoid system plays an important role in various liver diseases. Activin A is a member of the transforming growth factor beta (TGF-β) superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin A. This study was designed to investigate the effect of rimonabant (a potent cannabinoid receptor1 (CB1) antagonist) on NAFLD induced with a choline-deficient (CD) diet in rats, as well as to detect whether it can alter the hepatic expression of activin A and follistatin. Forty rats were distributed among 4 groups: the control group, the rimonabant treatment group (normal rats that received rimonabant); the CD diet group (NAFLD induced with a CD diet); and the CD diet + rimonabant group (NAFLD treated with rimonabant). It was found that the CD diet caused significant increase in liver index, serum levels of liver enzymes, malondialdehyde (MDA), TGF-β1, activin A, and CB1 expression in liver tissue, with a significant decrease in glutathione peroxidase (GSH-Px) and follistatin mRNA expression in liver tissues. The administration of rimonabant significantly improved all of the studied parameters compared with the group fed the CD diet alone. Histopathological examination supported these results. We concluded that rimonabant significantly counteracted NAFLD induced with the CD diet by decreasing oxidative stress and hepatic expression of TGF-β1, and modulating the hepatic expression of activin A and follistatin.