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생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
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Inactivation of Sirtuin2 protects mice from acetaminophen-induced liver injury: possible involvement of ER stress and S6K1 activation

  • Lee, Da Hyun (Brain Korea 21 PLUS Project for Medical Science, Yonsei University) ;
  • Lee, Buhyun (Brain Korea 21 PLUS Project for Medical Science, Yonsei University) ;
  • Park, Jeong Su (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Lee, Yu Seol (Brain Korea 21 PLUS Project for Medical Science, Yonsei University) ;
  • Kim, Jin Hee (Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine) ;
  • Cho, Yejin (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine) ;
  • Jo, Yoonjung (Department of Bioinspired Science, Ewha Womans University) ;
  • Kim, Hyun-Seok (Department of Bioinspired Science, Ewha Womans University) ;
  • Lee, Yong-ho (Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Nam, Ki Taek (Brain Korea 21 PLUS Project for Medical Science, Yonsei University) ;
  • Bae, Soo Han (Severance Biomedical Science Institute, Yonsei Biomedical Research Institute, Yonsei University College of Medicine)
  • 투고 : 2018.04.17
  • 심사 : 2018.07.13
  • 발행 : 2019.03.31
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초록

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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참고문헌

  1. Ghabril M, Chalasani N and Bjornsson E (2010) Drug-induced liver injury: a clinical update. Curr Opin Gastroenterol 26, 222-226 https://doi.org/10.1097/MOG.0b013e3283383c7c
  2. James LP, Mayeux PR and Hinson JA (2003) Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 31, 1499-1506 https://doi.org/10.1124/dmd.31.12.1499
  3. Ni HM, Williams JA, Yang H, Shi YH, Fan J and Ding WX (2012) Targeting autophagy for the treatment of liver diseases. Pharmacol Res 66, 463-474 https://doi.org/10.1016/j.phrs.2012.07.003
  4. Hinson JA, Roberts DW and James LP (2010) Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol, 369-405
  5. Copple IM, Goldring CE, Jenkins RE et al (2008) The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system. Hepatology 48, 1292-1301 https://doi.org/10.1002/hep.22472
  6. Nagy G, Kardon T, Wunderlich L et al (2007) Acetaminophen induces ER dependent signaling in mouse liver. Arch Biochem Biophys 459, 273-279 https://doi.org/10.1016/j.abb.2006.11.021
  7. Foufelle F and Fromenty B (2016) Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol Res Perspect 4, e00211 https://doi.org/10.1002/prp2.211
  8. Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273, 793-798 https://doi.org/10.1006/bbrc.2000.3000
  9. Morris BJ (2013) Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med 56, 133-171 https://doi.org/10.1016/j.freeradbiomed.2012.10.525
  10. Houtkooper RH, Pirinen E and Auwerx J (2012) Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol 13, 225-238 https://doi.org/10.1038/nrm3293
  11. Gomes P, Outeiro TF and Cavadas C (2015) Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism. Trends Pharmacol Sci 36, 756-768 https://doi.org/10.1016/j.tips.2015.08.001
  12. Craig DG, Bates CM, Davidson JS, Martin KG, Hayes PC and Simpson KJ (2011) Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity. Br J Clin Pharmacol 71, 273-282 https://doi.org/10.1111/j.1365-2125.2010.03819.x
  13. Outeiro TF, Kontopoulos E, Altmann SM et al (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516-519 https://doi.org/10.1126/science.1143780
  14. Rumpf T, Schiedel M, Karaman B et al (2015) Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun 6, 6263 https://doi.org/10.1038/ncomms7263
  15. Luthi-Carter R, Taylor DM Pallos J et al (2010) SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A 107, 7927-7932 https://doi.org/10.1073/pnas.1002924107
  16. Hu J, Ramshesh VK, McGill MR, Jaeschke H and Lemasters JJ (2016) Low Dose Acetaminophen Induces Reversible Mitochondrial Dysfunction Associated with Transient c-Jun N-Terminal Kinase Activation in Mouse Liver. Toxicol Sci 150, 204-215 https://doi.org/10.1093/toxsci/kfv319
  17. Ni HM, Williams JA, Jaeschke H and Ding WX (2013) Zonated induction of autophagy and mitochondrial spheroids limits acetaminophen-induced necrosis in the liver. Redox Biol 1, 427-432 https://doi.org/10.1016/j.redox.2013.08.005
  18. Lorz C, Justo P, Sanz A, Subira D, Egido J and Ortiz A (2004) Paracetamol-induced renal tubular injury: a role for ER stress. J Am Soc Nephrol 15, 380-389 https://doi.org/10.1097/01.ASN.0000111289.91206.B0
  19. Uzi D, Barda L, Scaiewicz V et al (2013) CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 59, 495-503 https://doi.org/10.1016/j.jhep.2013.04.024
  20. Kalinec GM, Thein P, Parsa A et al (2014) Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways. Hear Res 313, 26-37 https://doi.org/10.1016/j.heares.2014.04.007
  21. Bertolotti A, Zhang Y, Hendershot LM, Harding HP and Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2, 326-332 https://doi.org/10.1038/35014014
  22. Dong G, Liu Y, Zhang L, Huang S, Ding HF and Dong Z (2015) mTOR contributes to ER stress and associated apoptosis in renal tubular cells. Am J Physiol Renal Physiol 308, F267-274 https://doi.org/10.1152/ajprenal.00629.2014
  23. Wu M, Liu H, Fannin J et al (2010) Acetaminophen improves protein translational signaling in aged skeletal muscle. Rejuvenation Res 13, 571-579 https://doi.org/10.1089/rej.2009.1015
  24. Hong S, Zhao B, Lombard DB, Fingar DC and Inoki K (2014) Cross-talk between sirtuin and mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of S6 kinase 1 (S6K1) phosphorylation. J Biol Chem 289, 13132-13141 https://doi.org/10.1074/jbc.M113.520734
  25. Rack JG, VanLinden MR, Lutter T, Aasland R and Ziegler M (2014) Constitutive nuclear localization of an alternatively spliced sirtuin-2 isoform. J Mol Biol 426, 1677-1691 https://doi.org/10.1016/j.jmb.2013.10.027
  26. Mangas-Sanjuan V, Olah J, Gonzalez-Alvarez I et al (2015) Tubulin acetylation promoting potency and absorption efficacy of deacetylase inhibitors. Br J Pharmacol 172, 829-840 https://doi.org/10.1111/bph.12946
  27. Chopra V, Quinti L, Kim J et al (2012) The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models. Cell Rep 2, 1492-1497 https://doi.org/10.1016/j.celrep.2012.11.001
  28. Wu FL, Liu WY, Van Poucke S et al (2016) Targeting endoplasmic reticulum stress in liver disease. Expert Rev Gastroenterol Hepatol 10, 1041-1052 https://doi.org/10.1080/17474124.2016.1179575
  29. Malhi H and Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54, 795-809 https://doi.org/10.1016/j.jhep.2010.11.005
  30. Hay N and Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18, 1926-1945 https://doi.org/10.1101/gad.1212704
  31. Ni HM, Bockus A, Boggess N, Jaeschke H and Ding WX (2012) Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55, 222-232 https://doi.org/10.1002/hep.24690
  32. Borude P, Bhushan B, Gunewardena S, Akakpo J, Jaeschke H and Apte U (2018) Pleiotropic Role of p53 in Injury and Liver Regeneration after Acetaminophen Overdose. Am J Pathol 188, 1406-1418 https://doi.org/10.1016/j.ajpath.2018.03.006
  33. Chen W, Zhang X, Fan J et al (2017) Tethering Interleukin-22 to Apolipoprotein A-I Ameliorates Mice from Acetaminophen-induced Liver Injury. Theranostics 7, 4135-4148 https://doi.org/10.7150/thno.20955
  34. Wang J, Koh HW, Zhou L et al (2017) Sirtuin 2 aggravates postischemic liver injury by deacetylating mitogen-activated protein kinase phosphatase-1. Hepatology 65, 225-236 https://doi.org/10.1002/hep.28777
  35. Arteaga M, Shang N, Ding X et al (2016) Inhibition of SIRT2 suppresses hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 310, G1155-1168 https://doi.org/10.1152/ajpgi.00271.2015
  36. Lu Z, Bourdi M, Li JH et al (2011) SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity. EMBO Rep 12, 840-846 https://doi.org/10.1038/embor.2011.121
  37. Inoue T, Nakayama Y, Li Y et al (2014) SIRT2 knockdown increases basal autophagy and prevents postslippage death by abnormally prolonging the mitotic arrest that is induced by microtubule inhibitors. FEBS J 281, 2623-2637 https://doi.org/10.1111/febs.12810
  38. Park SH, Zhu Y, Ozden O et al (2012) SIRT2 is a tumor suppressor that connects aging, acetylome, cell cycle signaling, and carcinogenesis. Transl Cancer Res 1, 15-21
  39. Kim HS, Vassilopoulos A, Wang RH et al (2011) SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20, 487-499 https://doi.org/10.1016/j.ccr.2011.09.004
  40. Nie H, Chen H, Han J et al (2011) Silencing of SIRT2 induces cell death and a decrease in the intracellular ATP level of PC12 cells. Int J Physiol Pathophysiol Pharmacol 3, 65-70
  41. Hoffmann G, Breitenbucher F, Schuler M and Ehrenhofer-Murray AE (2014) A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer. J Biol Chem 289, 5208-5216 https://doi.org/10.1074/jbc.M113.487736