Sirtuin-activating compounds (STACs) alleviate D-galactosamine/lipopolysaccharide-induced hepatotoxicity in rats: Involvement of sirtuin 1 and heme oxygenase 1.

摘要

Sirtuin activating compounds (STACs) attenuate various type ofliver insults through mechanisms which are not fully understood.In the present study, we investigated the ameliorative potentialof quercetin (natural polyphenol) and SRT1720 (synthetic SIRT1activator) against D-galactosamine/lipopolysaccharide-inducedhepatotoxicity (an experimental model of acute liver failure).Moreover, we compared and contrasted the roles of stressresponsive enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1(HO-1) in hepatoprotection/ hepatotoxicity. Liver injury wasinduced in male Wistar rats by intraperitoneal injection ofD-galactosamine (400 mg/kg) and lipopolysaccharide (10 μg/kg).Some animals were pretreated with quercetin (50 mg/kg i.p.) orSRT1720 (5 mg/kg i.p.). Twenty-four hours later, the effects ofthese treatments were evaluated by biochemical studies andWestern blot. D-GalN/LPS treatment upregulatedHO-1 expression, downregulated SIRT1 expression, decreasedAST:ALT ratio and markedly increased bilirubin, catalase andconjugated diene levels. Pretreatment of D-GalN/LPS rats witheither quercetin or SRT1720 returned SIRT1 expression,HO-1 expression and all the aforementioned markers towardsnormal. Collectively, these findings suggest that elevated HO-1and low SIRT1 expressions are involved in the pathogenesis ofD-GalN/LPS-induced hepatotoxicity. Drugs that downregulateHO-1 and/or upregulate SIRT1 seem to have antihepatotoxiceffects and need further exploration.