Journal Article

Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6

Wang, Minhua, Wang, Kewei, Gannon, Maureen, Holterman, AiXuan

2016

Overview

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. 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. 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. GH broad protective actions on hepatocytes during liver injury are effected through Hnf6, with Hnf6 transcriptional activation of Ciap1 as an underlying molecular mediator.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal models / Animals / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Bile / Bile ducts / Biology and Life Sciences / Blotting, Western / Care and treatment / Caspase / Caspase 3 - genetics / Caspase 3 - metabolism / Caspase 8 - genetics / Caspase 8 - metabolism / Caspase 9 - genetics / Caspase 9 - metabolism / Cell death / Cells, Cultured / Cluster Analysis / Deoxyribonucleic acid / Development and progression / DNA / Fibrosis / Gallbladder diseases / Gene expression / Gene Expression - drug effects / Genetic aspects / Genetic testing / Growth hormone / Growth Hormone - pharmacology / Growth hormones / Health aspects / Hepatitis / Hepatocyte Nuclear Factor 6 - genetics / Hepatocyte Nuclear Factor 6 - metabolism / Hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Humans / Inhibitor of Apoptosis Proteins - genetics / Inhibitor of Apoptosis Proteins - metabolism / Injuries / Insulin-like growth factors / Lipopolysaccharides - pharmacology / Liver / Liver - cytology / Liver - drug effects / Liver - metabolism / Liver diseases / Medicine / Medicine and Health Sciences / Metabolism / Mice / Mice, Knockout / Pediatrics / Protective Agents - pharmacology / Protein Binding / Proteins / Research and Analysis Methods / Reverse Transcriptase Polymerase Chain Reaction / Rodents / Somatotropin / Surgery / Transcription activation / Transcription factors