title: Akt-mediated foxo1 inhibition is required for liver regeneration.
abstract: Understanding the hepatic regenerative process has clinical interest as the effectiveness of many treatments for chronic liver diseases is conditioned by efficient liver regeneration. Experimental evidence points to the need for a temporal coordination between cytokines, growth factors, and metabolic signaling pathways to enable successful liver regeneration. One intracellular mediator that acts as a signal integration node for these processes is the serine-threonine kinase Akt/protein kinase B (Akt). To investigate the contribution of Akt during hepatic regeneration, we performed partial hepatectomy in mice lacking Akt1, Akt2, or both isoforms. We found that absence of Akt1 or Akt2 does not influence liver regeneration after partial hepatectomy. However, hepatic-specific Akt1 and Akt2 null mice show impaired liver regeneration and increased mortality. The major abnormal cellular events observed in total Akt-deficient livers were a marked reduction in cell proliferation, cell hypertrophy, glycogenesis, and lipid droplet formation. Most importantly, liver-specific deletion of FoxO1, a transcription factor regulated by Akt, rescued the hepatic regenerative capability in Akt1-deficient and Akt2-deficient mice and normalized the cellular events associated with liver regeneration.
  
  
  CONCLUSIONS
  The Akt-FoxO1 signaling pathway plays an essential role during liver regeneration.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.|Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
authors.forename: Montse
authors.initials: M
authors.lastname: Pauta
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.|Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández-Hernando
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology and Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
authors.forename: Cedric
authors.initials: C
authors.lastname: Langhi
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ribera
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Lilly China Research and Development Center, Shanghai, People's Republic of China.
authors.forename: Mingjian
authors.initials: M
authors.lastname: Lu
authors.affiliation: Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Loreto
authors.initials: L
authors.lastname: Boix
authors.affiliation: Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.|Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain.
authors.forename: Wladimiro
authors.initials: W
authors.lastname: Jimenez
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.|Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology and Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology and Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
authors.forename: Angel
authors.initials: A
authors.lastname: Baldán
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.|Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Morales-Ruiz
authors.affiliation: Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.|Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.|Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000502:physiology; D000818:Animals; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D022781:Hepatocytes / Q000473:pathology; D006965:Hyperplasia; D050356:Lipid Metabolism; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D064413:3-Phosphoinositide-Dependent Protein Kinases; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; C578564:Pdpk1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt