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.