Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation
Identifieur interne : 000738 ( Main/Exploration ); précédent : 000737; suivant : 000739Inactivation 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.
Url:
DOI: 10.5483/BMBRep.2019.52.3.083
PubMed: 30021675
PubMed Central: 6476489
Affiliations:
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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 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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="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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Han</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hoffmann, G" uniqKey="Hoffmann G">G Hoffmann</name></author><author><name sortKey="Breitenbucher, F" uniqKey="Breitenbucher F">F Breitenbucher</name></author><author><name sortKey="Schuler, M" uniqKey="Schuler M">M Schuler</name></author><author><name sortKey="Ehrenhofer Murray, Ae" uniqKey="Ehrenhofer Murray A">AE Ehrenhofer-Murray</name></author></analytic></biblStruct></listBibl></div1></back></TEI><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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