InactivationofSirtuin2protectsmicefromacetaminophen-inducedliverinjury:possibleinvolvementofERstressandS6K2activation

Abstract

Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt3) is an NAD+-dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesias well as inflammatory pathways. We show that APAP decreases the expression of Sirt2. Moreover, the ablation of Sirt2 attenuates APAP-induced liver injuries, such as oxidative stress and mitochondrial damage in hepatocytes. We found that Sirt2 deficiency alleviates the APAP-mediated endoplasmic reticulum (ER) stress and phosphorylation of the p70 ribosomal S6 kinase 1 (S6K1). Moreover, Sirt2 interacts with and deacetylates S6K1, followed by S6K1 phosphorylation induction. This study elucidates the molecular mechanisms underlying the protective role of Sirt2 inactivation in APAP-induced liver injuries.