Non-structural 5A protein of hepatitis C virus induces a range of liver pathology in transgenic mice.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). However, the mechanism of HCV pathogenesis is not well understood. Our previous in vitro studies suggested that non-structural 5A (NS5A) protein may play an important role in liver pathogenesis. To elucidate the mechanism of HCV-induced liver pathogenesis, we investigated the histopathological changes of liver in transgenic mice harbouring the NS5A gene. We generated transgenic mice harbouring HCV NS5A gene under the control of hepatitis B virus (HBV) enhancer. Pathological changes were analysed by immunohistochemical staining and western blot analysis. Lipid composition and reactive oxygen species (ROS) production in NS5A transgenic mice were analysed. HCV NS5A transgenic mice developed extraordinary steatosis over 6 months old and induced HCC in some mice. NS5A was co-localized with apolipoprotein A-I in fatty hepatocytes. In addition, the extraordinarily high levels of ROS, NF-kappaB and STAT3 were detected in hepatocytes of NS5A transgenic mice. These data suggest that NS5A, independent of other HCV viral proteins, may play an important role in the development of hepatic pathologies, including steatosis and hepatoceullular carcinoma in transgenic mice.
Wang
Ai-Guo
AG
Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Lee
Dong-Seok
DS
Moon
Hyung-Bae
HB
Kim
Jin-Man
JM
Cho
Kyung-Hyun
KH
Choi
Soo-Ho
SH
Ha
Hye-Lin
HL
Han
Ying-Hao
YH
Kim
Dae-Ghon
DG
Hwang
Soon B
SB
Yu
Dae-Yeul
DY
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D005260:Female; D016174:Hepacivirus / Q000472:pathogenicity*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D014774:Virulence; D012324:RNA-Dependent RNA Polymerase
D016632:Apolipoprotein A-I; D005227:Fatty Acids; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase