title: Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6.
abstract: OBJECTIVE
  Growth hormone (GH) not only supports hepatic metabolism but also protects against hepatocyte cell death. Hnf6 (or Oc1) belonging to the Onecut family of hepatocyte transcription factors known to regulate differentiated hepatic function, is a GH-responsive gene. We evaluate if GH mediates Hnf6 activity to attenuate hepatic apoptotic injury.
  
  
  METHODS
  We used an animal model of hepatic apoptosis by bile duct ligation (BDL) with Hnf6 -/- (KO) mice in which hepatic Hnf6 was conditionally inactivated. GH was administered to adult wild type WT and KO mice for the 7 days of BDL to enhance Hnf6 expression. In vitro, primary hepatocytes derived from KO and WT liver were treated with LPS and hepatocyte apoptosis was assessed with and without GH treatment.
  
  
  RESULTS
  In WT mice, GH treatment enhanced Hnf6 expression during BDL, inhibited Caspase -3, -8 and -9 responses and diminished hepatic apoptotic and fibrotic injury. GH-mediated upregulation of Hnf6 expression and parallel suppression of apoptosis and fibrosis in WT BDL liver were abrogated in KO mice. LPS activated apoptosis and suppressed Hnf6 expression in primary hepatocytes. GH/LPS co-treatment enhanced Hnf6 expression with corresponding attenuation of apoptosis in WT-derived hepatocytes, but not in KO hepatocytes. ChiP-on-ChiP and electromobility shift assays of KO and WT liver nuclear extracts identified Ciap1 (or Birc2) as an Hnf6-bound target gene. Ciap1 expression patterns closely follow Hnf6 expression in the liver and in hepatocytes.
  
  
  CONCLUSIONS
  GH broad protective actions on hepatocytes during liver injury are effected through Hnf6, with Hnf6 transcriptional activation of Ciap1 as an underlying molecular mediator.
authors.affiliation: Department of Surgery/Pediatric Surgery, U of Illinois College of Medicine, Peoria, IL, United States of America.
authors.forename: Kewei
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Surgery/Pediatric Surgery, U of Illinois College of Medicine, Peoria, IL, United States of America.
authors.forename: Minhua
authors.initials: M
authors.lastname: Wang
authors.affiliation: Departments of Medicine/Molecular Physiology/Biophysics, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gannon
authors.affiliation: Department of Surgery/Pediatric Surgery, U of Illinois College of Medicine, Peoria, IL, United States of America.
authors.forename: AiXuan
authors.identifier: http://orcid.org/0000-0003-2819-7434
authors.initials: A
authors.lastname: Holterman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016000:Cluster Analysis; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology*; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018345:Mice, Knockout; D020011:Protective Agents / Q000494:pharmacology; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C107521:Birc4 protein, mouse; D051559:Hepatocyte Nuclear Factor 6; D051034:Inhibitor of Apoptosis Proteins; D008070:Lipopolysaccharides; C496606:Onecut1 protein, mouse; D020011:Protective Agents; D013006:Growth Hormone; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9