Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation
Identifieur interne : 000683 ( Pmc/Checkpoint ); précédent : 000682; suivant : 000684Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation
Auteurs : Da Hyun Lee [Corée du Sud] ; Buhyun Lee [Corée du Sud] ; Jeong Su Park [Corée du Sud] ; Yu Seol Lee [Corée du Sud] ; Jin Hee Kim [Corée du Sud] ; Yejin Cho [Corée du Sud] ; Yoonjung Jo [Corée du Sud] ; Hyun-Seok Kim [Corée du Sud] ; Yong-Ho Lee [Corée du Sud] ; Ki Taek Nam [Corée du Sud] ; Soo Han Bae [Corée du Sud]Source :
- BMB Reports [ 1976-6696 ] ; 2019.
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.
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DOI: 10.5483/BMBRep.2019.52.3.083
PubMed: 30021675
PubMed Central: 6476489
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country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Buhyun" sort="Lee, Buhyun" uniqKey="Lee B" first="Buhyun" last="Lee">Buhyun Lee</name><affiliation wicri:level="1"><nlm:aff id="af1-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Jeong Su" sort="Park, Jeong Su" uniqKey="Park J" first="Jeong Su" 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Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jin Hee" sort="Kim, Jin Hee" uniqKey="Kim J" first="Jin Hee" last="Kim">Jin Hee Kim</name><affiliation wicri:level="1"><nlm:aff id="af6-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cho, Yejin" sort="Cho, Yejin" uniqKey="Cho Y" first="Yejin" last="Cho">Yejin Cho</name><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jo, Yoonjung" sort="Jo, Yoonjung" uniqKey="Jo Y" first="Yoonjung" last="Jo">Yoonjung Jo</name><affiliation wicri:level="1"><nlm:aff id="af3-bmb-52-190">Department of Bioinspired Science, Ewha Womans University, Seoul 120-750,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Hyun Seok" sort="Kim, Hyun Seok" uniqKey="Kim H" first="Hyun-Seok" last="Kim">Hyun-Seok Kim</name><affiliation wicri:level="1"><nlm:aff id="af3-bmb-52-190">Department of Bioinspired Science, Ewha Womans University, Seoul 120-750,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Yong Ho" sort="Lee, Yong Ho" uniqKey="Lee Y" first="Yong-Ho" last="Lee">Yong-Ho Lee</name><affiliation wicri:level="1"><nlm:aff id="af4-bmb-52-190">Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-bmb-52-190">Institute of Endocrine Research, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nam, Ki Taek" sort="Nam, Ki Taek" uniqKey="Nam K" first="Ki Taek" last="Nam">Ki Taek Nam</name><affiliation wicri:level="1"><nlm:aff id="af1-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bae, Soo Han" sort="Bae, Soo Han" uniqKey="Bae S" first="Soo Han" last="Bae">Soo Han Bae</name><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30021675</idno><idno type="pmc">6476489</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476489</idno><idno type="RBID">PMC:6476489</idno><idno type="doi">10.5483/BMBRep.2019.52.3.083</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000414</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000414</idno><idno type="wicri:Area/Pmc/Curation">000414</idno><idno type="wicri:explorRef" wicri:stream="Pmc" 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Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Buhyun" sort="Lee, Buhyun" uniqKey="Lee B" first="Buhyun" last="Lee">Buhyun Lee</name><affiliation wicri:level="1"><nlm:aff id="af1-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Jeong Su" sort="Park, Jeong Su" uniqKey="Park J" first="Jeong Su" last="Park">Jeong Su Park</name><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Yu Seol" sort="Lee, Yu Seol" uniqKey="Lee Y" first="Yu Seol" last="Lee">Yu Seol Lee</name><affiliation wicri:level="1"><nlm:aff id="af1-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Jin Hee" sort="Kim, Jin Hee" uniqKey="Kim J" first="Jin Hee" last="Kim">Jin Hee Kim</name><affiliation wicri:level="1"><nlm:aff id="af6-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Cho, Yejin" sort="Cho, Yejin" uniqKey="Cho Y" first="Yejin" last="Cho">Yejin Cho</name><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jo, Yoonjung" sort="Jo, Yoonjung" uniqKey="Jo Y" first="Yoonjung" last="Jo">Yoonjung Jo</name><affiliation wicri:level="1"><nlm:aff id="af3-bmb-52-190">Department of Bioinspired Science, Ewha Womans University, Seoul 120-750,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Hyun Seok" sort="Kim, Hyun Seok" uniqKey="Kim H" first="Hyun-Seok" last="Kim">Hyun-Seok Kim</name><affiliation wicri:level="1"><nlm:aff id="af3-bmb-52-190">Department of Bioinspired Science, Ewha Womans University, Seoul 120-750,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Yong Ho" sort="Lee, Yong Ho" uniqKey="Lee Y" first="Yong-Ho" last="Lee">Yong-Ho Lee</name><affiliation wicri:level="1"><nlm:aff id="af4-bmb-52-190">Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-bmb-52-190">Institute of Endocrine Research, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nam, Ki Taek" sort="Nam, Ki Taek" uniqKey="Nam K" first="Ki Taek" last="Nam">Ki Taek Nam</name><affiliation wicri:level="1"><nlm:aff id="af1-bmb-52-190">Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bae, Soo Han" sort="Bae, Soo Han" uniqKey="Bae S" first="Soo Han" last="Bae">Soo Han Bae</name><affiliation wicri:level="1"><nlm:aff id="af2-bmb-52-190">Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">BMB Reports</title><idno type="ISSN">1976-6696</idno><idno type="eISSN">1976-670X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an NAD<sup>+</sup>-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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ghabril, M" uniqKey="Ghabril M">M Ghabril</name></author><author><name sortKey="Chalasani, N" uniqKey="Chalasani N">N Chalasani</name></author><author><name sortKey="Bjornsson, E" uniqKey="Bjornsson E">E Bjornsson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="James, Lp" uniqKey="James L">LP James</name></author><author><name sortKey="Mayeux, Pr" uniqKey="Mayeux P">PR Mayeux</name></author><author><name sortKey="Hinson, Ja" uniqKey="Hinson J">JA Hinson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ni, Hm" uniqKey="Ni H">HM Ni</name></author><author><name sortKey="Williams, Ja" uniqKey="Williams J">JA Williams</name></author><author><name sortKey="Yang, H" uniqKey="Yang H">H 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMB Rep</journal-id><journal-id journal-id-type="iso-abbrev">BMB Rep</journal-id><journal-title-group><journal-title>BMB Reports</journal-title></journal-title-group><issn pub-type="ppub">1976-6696</issn><issn pub-type="epub">1976-670X</issn><publisher><publisher-name>Korean Society for Biochemistry and Molecular Biology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30021675</article-id><article-id pub-id-type="pmc">6476489</article-id><article-id pub-id-type="doi">10.5483/BMBRep.2019.52.3.083</article-id><article-id pub-id-type="publisher-id">bmb-52-190</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Da Hyun</given-names></name><xref ref-type="aff" rid="af1-bmb-52-190">1</xref><xref ref-type="aff" rid="af2-bmb-52-190">2</xref><xref rid="fn1-bmb-52-190" ref-type="author-notes">#</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Buhyun</given-names></name><xref ref-type="aff" rid="af1-bmb-52-190">1</xref><xref ref-type="aff" rid="af2-bmb-52-190">2</xref><xref rid="fn1-bmb-52-190" ref-type="author-notes">#</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Jeong Su</given-names></name><xref ref-type="aff" rid="af2-bmb-52-190">2</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Yu Seol</given-names></name><xref ref-type="aff" rid="af1-bmb-52-190">1</xref><xref ref-type="aff" rid="af2-bmb-52-190">2</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Jin Hee</given-names></name><xref ref-type="aff" rid="af6-bmb-52-190">6</xref></contrib><contrib contrib-type="author"><name><surname>Cho</surname><given-names>Yejin</given-names></name><xref ref-type="aff" rid="af2-bmb-52-190">2</xref></contrib><contrib contrib-type="author"><name><surname>Jo</surname><given-names>Yoonjung</given-names></name><xref ref-type="aff" rid="af3-bmb-52-190">3</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Hyun-Seok</given-names></name><xref ref-type="aff" rid="af3-bmb-52-190">3</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Yong-ho</given-names></name><xref ref-type="aff" rid="af4-bmb-52-190">4</xref><xref ref-type="aff" rid="af5-bmb-52-190">5</xref><xref rid="c1-bmb-52-190" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Nam</surname><given-names>Ki Taek</given-names></name><xref ref-type="aff" rid="af1-bmb-52-190">1</xref><xref ref-type="aff" rid="af2-bmb-52-190">2</xref><xref rid="c1-bmb-52-190" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Bae</surname><given-names>Soo Han</given-names></name><xref ref-type="aff" rid="af2-bmb-52-190">2</xref><xref rid="c1-bmb-52-190" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-bmb-52-190"><label>1</label>Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></aff><aff id="af2-bmb-52-190"><label>2</label>Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></aff><aff id="af3-bmb-52-190"><label>3</label>Department of Bioinspired Science, Ewha Womans University, Seoul 120-750,<country>Republic of Korea</country></aff><aff id="af4-bmb-52-190"><label>4</label>Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></aff><aff id="af5-bmb-52-190"><label>5</label>Institute of Endocrine Research, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722,<country>Republic of Korea</country></aff><aff id="af6-bmb-52-190"><label>6</label>Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722,<country>Republic of Korea</country></aff><author-notes><corresp id="c1-bmb-52-190"><label>*</label>Corresponding authors. Soo Han Bae, Tel: +82-2-2228-0756; Fax: +82-2-2227-8129; E-mail: <email>soohanbae@yuhs.ac</email>; Ki Taek Nam, Tel: +82-2-2228-0754; Fax: +82-2-2227-8129; E-mail: <email>KITAEK@yuhs.ac</email>; Yong-ho Lee, Tel: +82-2-2228-1943; Fax: +82-2-393-6884; E-mail: <email>yholee@yuhs.ac</email></corresp><fn id="fn1-bmb-52-190"><label>#</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><month>3</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>31</day><month>3</month><year>2019</year></pub-date><volume>52</volume><issue>3</issue><fpage>190</fpage><lpage>195</lpage><history><date date-type="received"><day>17</day><month>4</month><year>2018</year></date><date date-type="rev-recd"><day>10</day><month>5</month><year>2018</year></date><date date-type="accepted"><day>13</day><month>7</month><year>2018</year></date></history><permissions><copyright-statement>Copyright © 2019 by the The Korean Society for Biochemistry and Molecular Biology</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0">http://creativecommons.org/licenses/by-nc/4.0</ext-link>) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an NAD<sup>+</sup>-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.</p></abstract><kwd-group><kwd>Acetaminophen</kwd><kwd>ER stress</kwd><kwd>Hepatotoxicity</kwd><kwd>S6K1</kwd><kwd>Sirtuin2</kwd></kwd-group></article-meta></front><floats-group><fig id="f1-bmb-52-190" orientation="portrait" position="float"><label>Fig. 1</label><caption><p>APAP decreases Sirt2 levels in the mouse liver and ablation of Sirt2 ameliorates APAP-induced liver injuries in mice. (A) The livers of mice intraperitoneally injected with vehicle or APAP (500 mg/kg) for the indicated times were isolated, and liver homogenates were subjected to immunoblotting for Sirt2 and β-actin (loading control). (B) qRT-PCR analysis for the determination of Sirt2 mRNA levels. (C, D) Densitometric analysis of immunoblots, similar to those in (A). Ten-week-old WT and Sirt2 KO mice were injected with APAP (500 mg/kg). (E) Representative images, H&E analysis (magnification, 100×). The small panel images are enlarged photographs from the boxed areas (magnification, 200×), Quantitation of necrotic areas on H&E-stained mouse liver sections. (F) TUNEL analysis of liver sections and quantitation of TUNEL analysis. (G) Serum levels of alanine transaminase (=GPT). (H) Serum levels of GOP. Investigation of the increased hepatotoxicity in mice treated with vehicle, APAP, or AGK2 (Sirt2 inhibitor). Ten-week-old WT and Sirt2 KO mice were injected with AGK2 (1 mg/kg) 2 h prior to APAP (500 mg/kg) administration, and plasma and livers were collected 12 h after APAP injection. (I) Representative images from H&E analysis and Quantitation of the necrotic area. (J) TUNEL analysis and Quantitation. (K) Serum levels of alanine transaminase (=GPT). (L) Serum levels of GOP. Data represent the mean ± SD from three independent experiments. *P < 0.05, **P < 0.01, N.S, not significant.</p></caption><graphic xlink:href="bmb-52-190f1"></graphic></fig><fig id="f2-bmb-52-190" orientation="portrait" position="float"><label>Fig. 2</label><caption><p>The inactivation of Sirt2 attenuates ER stress in APAP-induced liver injuries in mice. (A–D) The livers of mice intraperitoneally injected with vehicle or APAP (500 mg/kg) for the indicated times were isolated, and qRT-PCR analysis for the determination of Grp78, PERK, ATF4, and IRE1α mRNA levels. (E–H) Sirt2 WT or Sirt2 KO mice 12 h after an intraperitoneal injected with vehicle or APAP (500 mg/kg). qRT-PCR analysis for the determination of Grp78, PERK, ATF4, and IRE1α mRNA levels. (I–L) The livers of mice intraperitoneally injected with vehicle, APAP (500 mg/kg), and AGK2 (1 mg/kg) for 12 h were isolated, and qRT-PCR analysis for the determination of Grp78, PERK, ATF4, and IRE1α mRNA levels. Data represent the mean ± SD from three independent experiments. *P < 0.05.</p></caption><graphic xlink:href="bmb-52-190f2"></graphic></fig><fig id="f3-bmb-52-190" orientation="portrait" position="float"><label>Fig. 3</label><caption><p>The APAP-induced S6K1 phosphorylation is inhibited in the livers of Sirt2-inactivated mice. (A) The livers of mice intraperitoneally injected with vehicle or APAP (500 mg/kg) for the indicated times were isolated, and immunoblot analysis for p-S6K1, S6K1, p-S6, and S6. (B, C) Densitometric analysis. (D–F) Sirt2 WT or Sirt2 KO mice 12 h after an intraperitoneal injected with vehicle or APAP (500 mg/kg), immunoblot analysis for Sirt2, p-S6K1, S6K1, p-S6, and S6. Densitometric analysis (D). (G) The livers of mice intraperitoneally injected with vehicle, APAP (500 mg/kg), AGK2 (1 mg/kg) for 12 h were isolated, and immunoblot analyses for p-S6K1, S6K1, p-S6, and S6. (H, I) Densitometric analysis. Data represent the mean ± SD from three independent experiments. *P < 0.05.</p></caption><graphic xlink:href="bmb-52-190f3"></graphic></fig><fig id="f4-bmb-52-190" orientation="portrait" position="float"><label>Fig. 4</label><caption><p>Sirt2 regulates the phosphorylation of S6K1 through S6K1 deacetylation in APAP-treated mouse livers. Immunoblots of immunoprecipitates and whole-cell lysates from lysates of (A) HEK293 cells transfected with S6K1 and Flag-Sirt2 (F-SIRT2) vectors subjected to immunoprecipitation with an antibody against S6K1. (B) HEK293 cells transfected with an S6K1, F-SIRT2, and a Sirt2 (H187Y) catalytic dead mutant vector subjected to immunoprecipitation with antibodies against acetyllysine, S6K1, or Flag. (C) HEK293 cells transfected with an HA-S6K1 (H-S6K1) or a Flag-Sirt2 vector subjected to immunoprecipitation with antibodies against Flag. (D) HEK293 cells transfected with H-S6K1, F-SIRT2, and F-SIRT2 (H187Y) vectors subjected to immunoprecipitation with antibodies against acetyllysine, or HA. (E) Sirt2 WT or Sirt2 KO mouse livers, following treatment with APAP for 12 h, subjected to immunoprecipitation with an anti-S6K1 antibody. (F) Sirt2 WT mouse livers, following treatment with APAP or AGK2 for 12 h, subjected to immunoprecipitation with an with an antibody against S6K1.</p></caption><graphic xlink:href="bmb-52-190f4"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Corée du Sud</li></country></list><tree><country name="Corée du Sud"><noRegion><name sortKey="Lee, Da Hyun" sort="Lee, Da Hyun" uniqKey="Lee D" first="Da Hyun" last="Lee">Da Hyun Lee</name></noRegion><name sortKey="Bae, Soo Han" sort="Bae, Soo Han" uniqKey="Bae S" first="Soo Han" last="Bae">Soo Han Bae</name><name sortKey="Cho, Yejin" sort="Cho, Yejin" uniqKey="Cho Y" first="Yejin" last="Cho">Yejin Cho</name><name sortKey="Jo, Yoonjung" sort="Jo, Yoonjung" uniqKey="Jo Y" first="Yoonjung" last="Jo">Yoonjung Jo</name><name sortKey="Kim, Hyun Seok" sort="Kim, Hyun Seok" uniqKey="Kim H" first="Hyun-Seok" last="Kim">Hyun-Seok Kim</name><name sortKey="Kim, Jin Hee" sort="Kim, Jin Hee" uniqKey="Kim J" first="Jin Hee" last="Kim">Jin Hee Kim</name><name sortKey="Lee, Buhyun" sort="Lee, Buhyun" uniqKey="Lee B" first="Buhyun" last="Lee">Buhyun Lee</name><name sortKey="Lee, Buhyun" sort="Lee, Buhyun" uniqKey="Lee B" first="Buhyun" last="Lee">Buhyun Lee</name><name sortKey="Lee, Da Hyun" sort="Lee, Da Hyun" uniqKey="Lee D" first="Da Hyun" last="Lee">Da Hyun Lee</name><name sortKey="Lee, Yong Ho" sort="Lee, Yong Ho" uniqKey="Lee Y" first="Yong-Ho" last="Lee">Yong-Ho Lee</name><name sortKey="Lee, Yong Ho" sort="Lee, Yong Ho" uniqKey="Lee Y" first="Yong-Ho" last="Lee">Yong-Ho Lee</name><name sortKey="Lee, Yu Seol" sort="Lee, Yu Seol" uniqKey="Lee Y" first="Yu Seol" last="Lee">Yu Seol Lee</name><name sortKey="Lee, Yu Seol" sort="Lee, Yu Seol" uniqKey="Lee Y" first="Yu Seol" last="Lee">Yu Seol Lee</name><name sortKey="Nam, Ki Taek" sort="Nam, Ki Taek" uniqKey="Nam K" first="Ki Taek" last="Nam">Ki Taek Nam</name><name sortKey="Nam, Ki Taek" sort="Nam, Ki Taek" uniqKey="Nam K" first="Ki Taek" last="Nam">Ki Taek Nam</name><name sortKey="Park, Jeong Su" sort="Park, Jeong Su" uniqKey="Park J" first="Jeong Su" last="Park">Jeong Su Park</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Checkpoint/RBID.i -Sk "pubmed:30021675" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Checkpoint/biblio.hfd \
| NlmPubMed2Wicri -a ChloroquineV1
| This area was generated with Dilib version V0.6.33. |  |