title: Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis.
abstract: Growth hormone (GH) resistance and low serum levels of insulinlike growth factor 1 (IGF-1) are common features in human liver fibrosis and cirrhosis. Signal transducer and activator of transcription 5 (STAT5) controls several vital functions in the liver, including GH-mediated transcription of IGF-1. To investigate the role of STAT5 in liver fibrogenesis, we specifically deleted the Stat5a/b locus both in hepatocytes and cholangiocytes in the multidrug resistance gene 2 knockout (Mdr2(-/-)) mouse model of cholestasis. Double knockout mice develop an early and severe liver fibrosis phenotype, accompanied by perturbed expression of key regulators of bile acid homeostasis. Deletion of Stat5 resulted in GH resistance, and IGF-1 levels in serum were undetectable. We could observe reduced expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased numbers of apoptotic hepatocytes.
  
  
  CONCLUSIONS
  Our data suggest that loss of STAT5 sensitizes hepatocytes to bile acid-induced damage and apoptosis caused by disruption of GH-induced transcription of Igf-1 and down-regulation of hepatoprotective genes. These findings could contribute to the understanding of liver fibrosis and future treatment strategies for liver fibrosis.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Leander
authors.initials: L
authors.lastname: Blaas
authors.forename: Jan-Wilhelm
authors.initials: JW
authors.lastname: Kornfeld
authors.forename: Daniel
authors.initials: D
authors.lastname: Schramek
authors.forename: Monica
authors.initials: M
authors.lastname: Musteanu
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Judith
authors.initials: J
authors.lastname: Gumhold
authors.forename: Franziska
authors.initials: F
authors.lastname: van Zijl
authors.forename: Doris
authors.initials: D
authors.lastname: Schneller
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Gerda
authors.initials: G
authors.lastname: Egger
authors.forename: Markus
authors.initials: M
authors.lastname: Mair
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.forename: Robert
authors.initials: R
authors.lastname: Eferl
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Josef
authors.initials: J
authors.lastname: Penninger
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Emilio
authors.initials: E
authors.lastname: Casanova
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002779:Cholestasis / Q000150:complications*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics; D013006:Growth Hormone / Q000502:physiology*; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D066246:ErbB Receptors; D013006:Growth Hormone; D051559:Hepatocyte Nuclear Factor 6; D007334:Insulin-Like Growth Factor I; D050799:STAT5 Transcription Factor; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C496606:Onecut1 protein, mouse; C494093:Stat5a protein, mouse