title: The survival pathways phosphatidylinositol-3 kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt modulate liver regeneration through hepatocyte size rather than proliferation.
abstract: Liver regeneration comprises a series of complicated processes. The current study was designed to investigate the roles of phosphoinositide-dependent protein kinase 1 (PDK1)-associated pathways in liver regeneration after partial hepatectomy (PH) using liver-specific Pdk1-knockout (L-Pdk1KO) and Pdk1/STAT3 double KO (L-DKO) mice. There was no liver regeneration, and 70% PH was lethal in L-Pdk1KO mice. Liver regeneration was severely impaired equally in L-Pdk1KO and L-DKO mice, even after nonlethal 30% PH. There was no cell growth (measured as increase of cell size) after hepatectomy in L-Pdk1KO mice, although the post-PH mitotic response was the same as in controls. As expected, hepatectomy did not induce hepatic Akt-phosphorylation (Thr308) in L-Pdk1KO mice, and post-PH phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase (p70(S6K)), and S6 were also reduced. To examine the specific role of PDK1-associated signals, a "pif-pocket" mutant of PDK1, which allows PDK1 only to phosphorylate Akt, was used. Liver regeneration was recovered in L-Pdk1KO mice with a "pif-pocket" mutant of PDK1. This re-activated Akt in L-Pdk1KO mice liver and induced post-PH cell growth, without affecting cell proliferation. Further deletion of STAT3 (L-DKO mice) did not further deteriorate liver regeneration, although this certainly reduced post-PH mitotic response. These findings indicate that PDK1/Akt contribute to liver regeneration by regulating cell size. Regarding phosphatidylinositol-3 kinase (PI3-K), immediate upstream signal of PDK1, activation of PI3-K induced cell proliferation via STAT3 activation in the liver of L-Pdk1KO mice but did not improve impaired liver regeneration. This confirmed the pivotal role of PDK1 in liver regeneration and cell growth.
  
  
  CONCLUSIONS
  PDK1/Akt-mediated responsive cell growth is essential for normal liver regeneration after PH, especially when cell proliferation is impaired.
authors.affiliation: Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D049109:Cell Proliferation; D048429:Cell Size; D004789:Enzyme Activation; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology*; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C578564:Pdpk1 protein, mouse