title: Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis.
abstract: Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the GH receptor gene (Ghr(-/-), a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2(-/-)), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr(-/-);Mdr2(-/-) mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation, and increased collagen deposition relative to Mdr2(-/-) mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr(-/-);Mdr2(-/-) mice had a pronounced down-regulation of hepatoprotective genes Hnf6, Egfr, and Igf-1, and significantly increased levels of reactive oxygen species (ROS) and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr(-/-)) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis, and bile infarcts compared to their wild-type littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr(-/-);Mdr2(-/-) mice displayed a significant decrease in tumor incidence compared to Mdr2(-/-) mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver.
  
  
  CONCLUSIONS
  GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Patricia
authors.initials: P
authors.lastname: Stiedl
authors.forename: Robert
authors.initials: R
authors.lastname: McMahon
authors.forename: Leander
authors.initials: L
authors.lastname: Blaas
authors.forename: Victoria
authors.initials: V
authors.lastname: Stanek
authors.forename: Jasmin
authors.initials: J
authors.lastname: Svinka
authors.forename: Beatrice
authors.initials: B
authors.lastname: Grabner
authors.forename: Gernot
authors.initials: G
authors.lastname: Zollner
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Kessler
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Robert
authors.initials: R
authors.lastname: Eferl
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
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 / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000150:complications; D013006:Growth Hormone / Q000378:metabolism*; D022781:Hepatocytes / Q000502:physiology; D006706:Homeostasis; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D013006:Growth Hormone; D017382:Reactive Oxygen Species; D011986:Receptors, Somatotropin; D000097202:ATP-Binding Cassette Sub-Family B Member 4