TY - JOUR
T1 - Primary cirrhotic hepatocytes resist TGFβ-induced apoptosis through a ROS-dependent mechanism
AU - Black, Dalliah
AU - Bird, Mark A.
AU - Samson, Charles M.
AU - Lyman, Suzanne
AU - Lange, Patty A.
AU - Schrum, Laura W.
AU - Qian, Ting
AU - Lemasters, J. J.
AU - Brenner, David A.
AU - Rippe, Richard A.
AU - Behrns, Kevin E.
N1 - Funding Information:
This work was supported by National Institutes of Health (KEB; DK02640-1), the University of North Carolina Centre for Gastrointestinal Biology and Disease (T30 DK34987-17), and the American Digestive Health Foundation (KEB).
PY - 2004/6
Y1 - 2004/6
N2 - Background/Aims The cirrhotic liver manifests dysregulated hepatocyte growth by poor regenerative capacity, formation of regenerative nodules, and malignant transformation to hepatocellular carcinoma. The purpose of this study was to determine if dysregulated hepatocyte growth occurs through deficient apoptosis. Methods Hepatocytes were isolated from normal and CCl 4-treated mice and treated with TGFβ, TNFα, and UV-C, known apoptotic agents. Results Cirrhotic hepatocytes were less sensitive to TGFβ- (45±5 vs. 15±3%; P<0.003), TNFα- (59±21 vs. 21±8%; P=0.02), and UV-C-induced (31±4 vs. 17±4%; P<0.03) apoptosis compared to normal hepatocytes. In normal hepatocytes, TGFβ-induced apoptosis occurred through a ROS-, MPT-, and caspase-dependent pathway. Cirrhotic hepatocytes lacked caspase activation, had decreased procaspase-8 expression, failed to undergo the MPT, and had increased basal ROS activity compared to normal hepatocytes. After treatment with trolox, an antioxidant that reduced basal ROS activity, cirrhotic hepatocytes underwent apoptosis in response to TGFβ treatment. Conclusions These findings suggest that increased ROS activity in cirrhotic hepatocytes plays a critical role in mediating cirrhotic hepatocyte resistance to apoptosis. Cirrhotic hepatocyte resistance to TGFβ-induced apoptosis is ROS-dependent and is a mechanism of dysregulated growth in the chronically inflamed liver.
AB - Background/Aims The cirrhotic liver manifests dysregulated hepatocyte growth by poor regenerative capacity, formation of regenerative nodules, and malignant transformation to hepatocellular carcinoma. The purpose of this study was to determine if dysregulated hepatocyte growth occurs through deficient apoptosis. Methods Hepatocytes were isolated from normal and CCl 4-treated mice and treated with TGFβ, TNFα, and UV-C, known apoptotic agents. Results Cirrhotic hepatocytes were less sensitive to TGFβ- (45±5 vs. 15±3%; P<0.003), TNFα- (59±21 vs. 21±8%; P=0.02), and UV-C-induced (31±4 vs. 17±4%; P<0.03) apoptosis compared to normal hepatocytes. In normal hepatocytes, TGFβ-induced apoptosis occurred through a ROS-, MPT-, and caspase-dependent pathway. Cirrhotic hepatocytes lacked caspase activation, had decreased procaspase-8 expression, failed to undergo the MPT, and had increased basal ROS activity compared to normal hepatocytes. After treatment with trolox, an antioxidant that reduced basal ROS activity, cirrhotic hepatocytes underwent apoptosis in response to TGFβ treatment. Conclusions These findings suggest that increased ROS activity in cirrhotic hepatocytes plays a critical role in mediating cirrhotic hepatocyte resistance to apoptosis. Cirrhotic hepatocyte resistance to TGFβ-induced apoptosis is ROS-dependent and is a mechanism of dysregulated growth in the chronically inflamed liver.
KW - AdIκB-SR, adenovirus IκB super-repressor
KW - AdLuc, adenovirus luciferase
KW - Apoptosis
KW - CCl, carbon tetrachloride
KW - Caspase
KW - CyA, cyclosporin A
KW - Mitochrondria permeability transition
KW - Reactive oxygen species
KW - Transforming growth factor beta
UR - http://www.scopus.com/inward/record.url?scp=2442719968&partnerID=8YFLogxK
U2 - 10.1016/S0168-8278(04)00128-X
DO - 10.1016/S0168-8278(04)00128-X
M3 - Article
C2 - 15158334
AN - SCOPUS:2442719968
SN - 0168-8278
VL - 40
SP - 942
EP - 951
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -