title: Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy.
abstract: OBJECTIVE
  Liver regeneration after partial hepatectomy (PH) occurs in conditions of reduced oxygen supply. HIF prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) are oxygen sensors involved in adaptive response to hypoxia. Specific functions of these PHD enzymes in liver regeneration have, however, remained enigmatic. Here, we investigated the significance of PHD1 in liver regeneration following hepatectomy.
  
  
  METHODS
  Liver regeneration was studied in PHD1-deficient (PHD1(-/-)) and wild type (WT) mice subjected to 80% hepatectomy. For in vitro analyses, hepatocytes were isolated from PHD1(-/-) and WT livers. Cell cycle progression was studied via FACS-based analysis of nuclear DNA profile. Transcription factor binding assays, qRT-PCR, and immunoblotting were applied to study the relevance of PHD1 downstream effectors during liver regeneration.
  
  
  RESULTS
  Liver regeneration was significantly enhanced in PHD1(-/-) mice compared to WT littermates. This effect was due to enhanced proliferation rather than to hypertrophy of liver cells. Cell cycle progression was significantly enhanced, and transcriptional activity of the cell cycle regulator c-Myc was increased in PHD1-deficient hepatocytes. These changes coincided with increased expression of cyclin D2, a cell cycle-promoting c-Myc target, and decreased expression of the cell cycle-delaying c-Myc target p21.
  
  
  CONCLUSIONS
  Loss of PHD1 enhances liver regeneration by boosting hepatocyte proliferation in a c-Myc-dependent fashion. PHD1 might, therefore, represent a potential target to facilitate liver regeneration after surgical resection.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mollenhauer
authors.forename: Judit
authors.initials: J
authors.lastname: Kiss
authors.forename: Johanna
authors.initials: J
authors.lastname: Dudda
authors.forename: Johanna
authors.initials: J
authors.lastname: Kirchberg
authors.forename: Nuh
authors.initials: N
authors.lastname: Rahbari
authors.forename: Praveen
authors.initials: P
authors.lastname: Radhakrishnan
authors.forename: Thomas
authors.initials: T
authors.lastname: Niemietz
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rausch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency* / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D011393:Procollagen-Proline Dioxygenase; D016271:Proto-Oncogene Proteins c-myc; D000099162:Endothelial PAS Domain-Containing Protein 1; C522721:PHD1 protein, mouse