TY - JOUR
T1 - Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice
AU - Tumurbaatar, Batbayar
AU - Sun, Yixiao
AU - Chan, Tehsheng
AU - Sun, Jiaren
N1 - Funding Information:
We gratefully acknowledge Stanley Lemon and Steve Weinman for helpful discussions; Francis Bodola for assisting in real-time PCR assays; Kui Li and Jingwu Xie for antibodies; Wendell Tang for his pathological expertise in histopathological analyses; Robert Davey and Lynn Soong for critical reading of the manuscript; Junhui Jia and Gueorgui Dubrocq for technical assistance and Ms. Mardelle Susman for assistance with manuscript preparation. This work was supported by grants from the National Institutes of Health (AI69142, AI60560 and AI40035), the UTMB Gastrointestinal Research Interdisciplinary Program, the Texas Gulf Coast Digestive Diseases Center (DK56338), and the UTMB Center for Population Health and Health Disparities.
PY - 2007/12
Y1 - 2007/12
N2 - Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK-18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.
AB - Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK-18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.
KW - Animal model and liver injury
KW - Transgenic mouse
KW - Viral hepatitis
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U2 - 10.1016/j.jviromet.2007.05.025
DO - 10.1016/j.jviromet.2007.05.025
M3 - Article
C2 - 17628708
AN - SCOPUS:35649028639
SN - 0166-0934
VL - 146
SP - 5
EP - 13
JO - Journal of Virological Methods
JF - Journal of Virological Methods
IS - 1-2
ER -