OBJECTIVE: Quercetin, a plant flavonoid with potent antioxidant action, has been shown to be ameliorative against different types of liver insults, including D-Galactosamine/Lipopolysaccharide (D-GalN/LPS). The notion that its cytoprotective effects are SIRT1 mediated is still controversial. In this work, we examined whether the synthetic allosteric SIRT1 activator, SRT1720, may similarly attenuate D-GalN/LPS-induced hepatotoxicity. MATERIALS AND METHODS: Male Wistar rats were randomly assigned into 6 groups: (1) Control, (2) Quercetin, (3) SRT1720, (4) D-GalN/LPS, (5) Quercetin + D-GalN/LPS and (6) SRT1720 + D-GalN/LPS. After twenty-four hours, the effects of these treatments were evaluated by biochemical studies, real-time PCR and Western blot. RESULTS: D-GalN/LPS treatment downregulated SIRT1 expression and markedly increased the aminotransferase, bilirubin and conjugated diene levels. Conversely, quercetin and SRT1720 pretreatments upregulated SIRT1 expression and decreased the levels of the aforementioned markers. Quercetin had more profound effect on SIRT1 expression than SRT1720. Moreover, quercetin was more efficacious than SRT1720 in combatting the cytotoxic effects of D-GalN/LPS, as evidenced by lower markers of liver injury. CONCLUSIONS: These results strongly suggest the involvement of SIRT1 in the cytoprotective effects of quercetin and SRT1720 against D-GalN/LPS-induced hepatotoxicity.

Institute of Pharmacology 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Czech Republic

SIRT1 Modulators in Experimentally Induced Liver Injury