Da Hyun Lee ; Buhyun Lee ; Jeong Su Park ; Yu Seol Lee ; Jin Hee Kim ; Yejin Cho ; Yoonjung Jo ; Hyun-Seok Kim ; Yong-ho Lee ; Ki Taek Nam ; Soo Han Bae
Acetaminophen/adverse effects ; Acetaminophen/pharmacology ; Acetaminophen/toxicity ; Animals ; Chemical and Drug InducedLiverInjury/genetics ; Chemical and Drug InducedLiverInjury/prevention & control ; Endoplasmic ReticulumStress/physiology ; Hepatocytes/metabolism ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria,Liver/metabolism ; Necrosis ; OxidativeStress ; Protective Agents ; Ribosomal Protein S6 Kinases, 90-kDa/metabolism ; Ribosomal Protein S6 Kinases, 90-kDa/physiology ; Sirtuin 2/genetics ; Sirtuin 2/metabolism ; Sirtuin 2/physiology
Keywords
Acetaminophen ; ER stress ; Hepatotoxicity ; S6K1 ; Sirtuin3
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.