Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: Possible involvement of ER stress and S6K1 activation

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

doi:10.5483/BMBRep.2019.52.3.083

Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: Possible involvement of ER stress and S6K1 activation

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

Department of Life Science

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 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.

Original language	English
Pages (from-to)	190-195
Number of pages	6
Journal	BMB Reports
Volume	52
Issue number	3
DOIs	https://doi.org/10.5483/BMBRep.2019.52.3.083
State	Published - 2019

Bibliographical note

Funding 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).

Publisher Copyright:
© 2019 by the The Korean Society for Biochemistry and Molecular Biology.

Keywords

Acetaminophen
ER stress
Hepatotoxicity
S6K1
Sirtuin2

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10.5483/BMBRep.2019.52.3.083

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@article{ac31d601c4394b6ba336783e63ed9025,

title = "Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: Possible involvement of ER stress and S6K1 activation",

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 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.",

keywords = "Acetaminophen, ER stress, Hepatotoxicity, S6K1, Sirtuin2",

author = "Lee, {Da Hyun} and Buhyun Lee and Park, {Jeong Su} and Lee, {Yu Seol} and Kim, {Jin Hee} and Yejin Cho and Yoonjung Jo and Kim, {Hyun Seok} and Lee, {Yong Ho} and Nam, {Ki Taek} and Bae, {Soo Han}",

note = "Funding 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). Publisher Copyright: {\textcopyright} 2019 by the The Korean Society for Biochemistry and Molecular Biology.",

year = "2019",

doi = "10.5483/BMBRep.2019.52.3.083",

language = "English",

volume = "52",

pages = "190--195",

journal = "BMB Reports",

issn = "1976-6696",

publisher = "The Biochemical Society of the Republic of Korea",

number = "3",

}

TY - JOUR

T1 - Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury

T2 - Possible involvement of ER stress and S6K1 activation

AU - Lee, Da Hyun

AU - Lee, Buhyun

AU - Park, Jeong Su

AU - Lee, Yu Seol

AU - Kim, Jin Hee

AU - Cho, Yejin

AU - Jo, Yoonjung

AU - Kim, Hyun Seok

AU - Lee, Yong Ho

AU - Nam, Ki Taek

AU - Bae, Soo Han

N1 - Funding 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). Publisher Copyright: © 2019 by the The Korean Society for Biochemistry and Molecular Biology.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Acetaminophen

KW - ER stress

KW - Hepatotoxicity

KW - S6K1

KW - Sirtuin2

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U2 - 10.5483/BMBRep.2019.52.3.083

DO - 10.5483/BMBRep.2019.52.3.083

M3 - Article

C2 - 30021675

AN - SCOPUS:85063768204

SN - 1976-6696

VL - 52

SP - 190

EP - 195

JO - BMB Reports

JF - BMB Reports

IS - 3

ER -

Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: Possible involvement of ER stress and S6K1 activation

Abstract

Bibliographical note

Keywords

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