Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an NAD+-dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesis, as 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.
Bibliographical noteFunding Information:
We thank Dr. Chu-Xia Deng, Dr. S. G Rhee, and Dr. J. H. Ryu for providing the Sirt2 WT and Sirt2 KO mice. In addition, we thank S. H. Sung and S. Y. Oh for maintaining the Sirt2 WT and Sirt2 KO mice. This work was supported by the National Research Foundation of Korea (NRF-2017R1A2B4007400; S. H. Bae, NRF-2017R1D1A1B03032808; J. S. Park, NRF-2016R 1A5A1010764; 2015R1C1A1A01052558; Y. H. Lee) and a Faculty Research Grant from the Yonsei University College of Medicine (6-2014-0068; 6-2015-0099; S. H. Bae). It was also supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0913; HI16C0257; S. H. Bae, HI14C2476; Y. H. Lee). This research was also supported by the Korea Mouse Phenotyping Project (NRF-2016M3A9D 5A01952416) from the National Research Foundation, by the Bio & Medical Technology Development Program of the NRF, funded by the Korean government (NRF-2017M3A9F3041234, NRF-2017R1A2B2009850) and the Brain Korea 21 PLUS Project for Medical Science, Yonsei University (to K. T. Nam).
All Science Journal Classification (ASJC) codes
- Molecular Biology