Laboratory Investigation (2010) 90, 1718–1726; doi:10.1038/labinvest.2010.119; published online 21 June 2010
Special Issue – Hepatic and Pancreatic Systems
p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism
Sanae Haga1,2, Naoki Morita3, Kaikobad Irani4, Masato Fujiyoshi1, Tetsuya Ogino5, Takeaki Ozawa6 and Michitaka Ozaki1
1. 1Department of Molecular Surgery, Hokkaido University School of Medicine, Sapporo, Japan
2. 2The Japan Society for the Promotion of Science (JSPS), Tokyo, Japan
3. 3Research Institute of Genome-based Biofactory, National Institute of Advanced Industrial Science and Technology (AIST), Sapporo, Japan
4. 4Cardiovascular Institute, University of Pittsburgh Medical Center, PA, USA
5. 5Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
6. 6Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan
Correspondence: Professor M Ozaki MD, PhD, Department of Molecular Surgery, Hokkaido University School of Medicine, N-15, W-7, Kita-ku, Sapporo, Hokkaido 060-8638 Japan. E-mail: firstname.lastname@example.org or email@example.com
Received 5 March 2010; Revised 5 May 2010; Accepted 11 May 2010; Published online 21 June 2010.
Liver regeneration involves complicated processes and is affected by various patho-physiological conditions. This 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 (mitogen-activated protein kinase, STAT3, p46/52Shc) and anti-oxidation (catalase, superoxide dismutase, Ref-1, glutathione peroxidase) 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 have a pivotal function in the impairment of liver regeneration in aged mice by triggering OS and subsequent apoptosis. This data may provide a clue to understanding the mechanism underlying the association between aging and the impairment of liver regeneration.
Akt; apoptosis; caspase-3; in vivo imaging; oxidative stress; p66Shc
Laboratory Investigation - p66Shc has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism