1. Increased liver pathology in hepatitis C virus transgenic mice expressing the hepatitis B virus X protein.
- Author
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Keasler VV, Lerat H, Madden CR, Finegold MJ, McGarvey MJ, Mohammed EM, Forbes SJ, Lemon SM, Hadsell DL, Grona SJ, Hollinger FB, and Slagle BL
- Subjects
- Animals, Hepacivirus genetics, Hepatitis C genetics, Liver drug effects, Liver metabolism, Liver virology, Mice, Mice, Transgenic, Viral Regulatory and Accessory Proteins, Hepacivirus physiology, Hepatitis C pathology, Liver pathology, Trans-Activators metabolism
- Abstract
Transgenic mice expressing the full-length HCV coding sequence were crossed with mice that express the HBV X gene-encoded regulatory protein HBx (ATX mice) to test the hypothesis that HBx expression accelerates HCV-induced liver pathogenesis. At 16 months (mo) of age, hepatocellular carcinoma was identified in 21% of HCV/ATX mice, but in none of the single transgenic animals. Analysis of 8-mo animals revealed that, relative to HCV/WT mice, HCV/ATX mice had more severe steatosis, greater liver-to-body weight ratios, and a significant increase in the percentage of hepatocytes staining for proliferating cell nuclear antigen. Furthermore, primary hepatocytes from HCV, ATX, and HCV/ATX transgenic mice were more resistant to fas-mediated apoptosis than hepatocytes from nontransgenic littermates. These results indicate that HBx expression contributes to increased liver pathogenesis in HCV transgenic mice by a mechanism that involves an imbalance in hepatocyte death and regeneration within the context of severe steatosis.
- Published
- 2006
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