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Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation
Soo Han Bae2,*, Da Hyun Lee1,2,#, Buhyun Lee1,2,#, Jeong Su Park2, Yu Seol Lee1,2, Jin Hee Kim6, Yejin Cho2, Yoonjung Jo3, Hyun-Seok Kim3, Yong-ho Lee4,5, Ki Taek Nam1,2
1Brain Korea 21 PLUS Project for Medical Science, Yonsei University,
2Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea,
3Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea,
4Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea,
5Institute of Endocrine Research, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea,
6Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
Abstract
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 Sirtuin2 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 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.
Abstract, Accepted Manuscript(in press) [Submitted on April 17, 2018, Accepted on July 13, 2018]
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