Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus

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  • Lerat, Hervé
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Honda, Masao
    • Other Affiliation: First Department of Internal Medicine, Kanazawa University, Kanazawa 920, Japan
  • Beard, Michael R.
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Loesch, Kim
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Sun, Jiaren
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Yang, Yan
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Okuda, Michiari
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Gosert, Rainer
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
  • Xiao, Shu-Yuan
    • Other Affiliation: Department of Pathology, The University of Texas Medical Branch, Galveston, Texas
  • Weinman, Steven A.
    • Other Affiliation: Departments of Internal Medicine and Physiology & Biophysics, The University of Texas Medical Branch, Galveston, Texas
  • Lemon, Stanley M.
    • Other Affiliation: Departments of Microbiology & Immunology, The University of Texas Medical Branch, Galveston, Texas
Abstract
  • Background and Aims: The aim of this study was to determine whether expression of hepatitis C virus proteins alters hepatic morphology or function in the absence of inflammation. Methods: Transgenic C57BL/6 mice with liver-specific expression of RNA encoding the complete viral polyprotein (FL-N transgene) or viral structural proteins (S-N transgene) were compared with nontransgenic littermates for altered liver morphology and function. Results: FL-N transcripts were detectable only by reverse-transcription polymerase chain reaction, and S-N transcripts were identified in Northern blots. The abundance of viral proteins was sufficient for detection only in S-N transgenic animals. There was no inflammation in transgenic livers, but mice expressing either transgene developed age-related hepatic steatosis that was more severe in males. Apoptotic or proliferating hepatocytes were not significantly increased. Hepatocellular adenoma or carcinoma developed in older male animals expressing either transgene, but their incidence reached statistical significance only in FL-N animals. Neither was ever observed in age-matched nontransgenic mice. Conclusions: Constitutive expression of viral proteins leads to common pathologic features of hepatitis C in the absence of specific anti-viral immune responses. Expression of the structural proteins enhances a low background of steatosis in C57BL/6 mice, while additional low level expression of nonstructural proteins increases the risk of cancer.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Gastroenterology
Journal volume
  • 122
Journal issue
  • 2
Page start
  • 352
Page end
  • 365
Language
  • English
Version
  • Postprint
ISSN
  • 0016-5085

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