title: Pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background.
abstract: BACKGROUND
  While the immune pathogenesis caused by hepatitis B virus (HBV) infection has been studied extensively, little is known about direct pathogenic effects of HBV surface proteins. Here, we have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background.
  
  
  METHODS
  The impact of HBV surface protein expression on the liver was studied in two mouse strains, BALB/c and C57BL/6. Histology and hydroxyproline assays were performed to investigate liver morphology and fibrosis. Gene expression and signaling were analyzed by microarray, qPCR and Western blotting.
  
  
  RESULTS
  Expression of HBV surface proteins in the liver of transgenic mice induced activation of protein kinase-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (eIF2α) phosphorylation. Phosphorylation of eIF2α resulted in activation of the ER stress markers glucose regulated protein (GRP) 78 and pro-apoptotic C/EBP homologous protein (CHOP) in transgenic mice on BALB/c genetic background leading to stronger liver injury and fibrosis in comparison with transgenic mice on C57BL/6 background. Hepatic stellate cells represented the main collagen-producing liver cells in HBV transgenic mice. The key regulators of hepatocyte proliferation, transcription factors c-Jun and STAT3 were activated in HBV transgenic mice. Tumour incidence in transgenic mice was strain- and sex-dependent.
  
  
  CONCLUSIONS
  Extent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background.
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Churin
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stiefel
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Würger
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schröder
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Matono
authors.affiliation: Core Facility Microarray, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.affiliation: Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Montalbano
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Malvika
authors.initials: M
authors.lastname: Pompaiah
authors.affiliation: Central Laboratory Animal Facility, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Reifenberg
authors.affiliation: Division of Animal Welfare and Ethology, Justus Liebig University, Giessen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zahner
authors.affiliation: Institute for Surgical Research, Philipps University of Marburg, Marburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ocker
authors.affiliation: Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Gerlich
authors.affiliation: Institute of Medical Virology, National Reference Centre for Hepatitis B and D Viruses, Justus Liebig University, Giessen, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Glebe
authors.affiliation: Department of Gastroenterology, Justus Liebig University, Giessen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006509:Hepatitis B / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006515:Hepatitis B virus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D015398:Signal Transduction; D015678:Viral Structural Proteins / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015678:Viral Structural Proteins; D019892:eIF-2 Kinase