title: D-galactosamine/lipopolysaccharide-induced hepatotoxicity downregulates sirtuin 1 in rat liver: role of sirtuin 1 modulation in hepatoprotection.
abstract: D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.
authors.affiliation: Institute of Pharmacology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. mighty.kemelo@lf1.cuni.cz.
authors.forename: M K
authors.initials: MK
authors.lastname: Kemelo
authors.forename: L
authors.initials: L
authors.lastname: Wojnarová
authors.forename: N
authors.initials: N
authors.lastname: Kutinová Canová
authors.forename: H
authors.initials: H
authors.lastname: Farghali
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection; D004195:Disease Models, Animal; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005688:Galactosamine; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D017208:Rats, Wistar; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000975:Antioxidants; D002227:Carbazoles; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D013267:Stilbenes; D005688:Galactosamine; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol