title: Suppression of autophagy during liver regeneration impairs energy charge and hepatocyte senescence in mice.
abstract: Autophagy is a homeostatic mechanism that regulates protein and organelle turnover and uses the amino acids from degraded proteins to produce adenosine 5'-triphosphate (ATP). We investigated the activity of autophagy-associated pathways in liver regeneration after partial hepatectomy (PHx) in liver-specific autophagy-related gene 5 (Atg5) knockout (KO) mice. Liver regeneration was severely impaired by 70% PHx, with a reduction in postoperative mitosis, but a compensating increase in hepatocyte size. PHx induced intracellular adenosine triphosphate and β-oxidation reduction as well as injured cellular mitochondria. Furthermore, PHx in Atg5 KO mice enhanced hepatic accumulation of p62 and ubiquitinated proteins. These results indicated that reorganization of intracellular proteins and organelles during autophagy was impaired in the regenerating liver of these mice. Up-regulation of p21 was associated with hepatocyte senescence, senescence-associated β-galactosidase expression, irreversible growth arrest, and secretion of senescence-associated molecules, including interleukin (IL)-6 and IL-8.
  
  
  CONCLUSIONS
  These findings indicate that autophagy plays a critical role in liver regeneration and in the preservation of cellular quality, preventing hepatocytes from becoming fully senescent and hypertrophic.
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Toshima
authors.forename: Ken
authors.initials: K
authors.lastname: Shirabe
authors.forename: Takasuke
authors.initials: T
authors.lastname: Fukuhara
authors.forename: Toru
authors.initials: T
authors.lastname: Ikegami
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yoshizumi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Soejima
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ikeda
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D016922:Cellular Senescence / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008938:Mitosis / Q000502:physiology
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D015850:Interleukin-6; D016209:Interleukin-8; D008869:Microtubule-Associated Proteins; C577686:interleukin-6, mouse