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p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism

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Title: p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism
Authors: Haga, Sanae Browse this author
Morita, Naoki Browse this author
Irani, Kaikobad Browse this author
Fujiyoshi, Masato Browse this author
Ogino, Tetsuya Browse this author
Ozawa, Takeaki Browse this author
Ozaki, Michitaka Browse this author
Keywords: Akt
in vivo imaging
oxidative stress
Issue Date: Dec-2010
Publisher: Nature Publishing Group
Journal Title: Laboratory Investigation
Volume: 90
Issue: 12
Start Page: 1718
End Page: 1726
Publisher DOI: 10.1038/labinvest.2010.119
PMID: 20567235
Abstract: Liver regeneration involves complicated processes and is affected by various patho-physiological conditions. The present study was designed to examine the molecular mechanisms underlying the aging-associated impairment of liver regeneration. Male C57BL/6J mice were used as young and aged mice (<10 weeks and >20 months old, respectively). These mice were subjected to 70% partial hepatectomy (PH). Liver regeneration and liver injury/stresses were evaluated chronologically after PH. Post-hepatectomy liver regeneration was markedly impaired in aged mice. Though the extent of hepatocyte proliferation in the regenerating liver was similar in aged and young mice, cell growth was absent in aged mice. Oxidative stress (OS) was observed immediately after hepatectomy, followed by marked apoptosis in aged mice. Signaling molecules regarding cell proliferation (MAPK, STAT-3, p46/52Shc) and anti-oxidation (catalase, SOD, Ref-1, GPx) were expressed/activated after hepatectomy in livers of both aged and young mice. Akt was not activated in aged-mouse liver, but its expression was similar to that in young mice. p66Shc, known as an age-/oxidant-associated protein, was strongly phosphorylated. By knocking-down p66Shc, the impairment of liver regeneration was normalized. OS immediately after hepatectomy induced subsequent liver injury (apoptosis), and deletion of p66Shc suppressed both OS and hepatocyte apoptosis in the regenerating liver of aged mice. Though we need additional data in other animal models to fully understand the mechanism, p66Shc may play a pivotal role in the impairment of liver regeneration in aged mice by triggering OS and subsequent apoptosis. The present data may provide a clue to understanding the mechanism underlying the association between aging and the impairment of liver regeneration.
Type: article (author version)
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 尾崎 倫孝

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