Primary cirrhotic hepatocytes resist TGFbeta-induced apoptosis through a ROS-dependent mechanism
- PMID: 15158334
- DOI: 10.1016/j.jhep.2004.02.031
Primary cirrhotic hepatocytes resist TGFbeta-induced apoptosis through a ROS-dependent mechanism
Abstract
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 TGFbeta, TNFalpha, and UV-C, known apoptotic agents.
Results: Cirrhotic hepatocytes were less sensitive to TGFbeta- (45+/-5 vs. 15+/-3%; P<0.003), TNFalpha- (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, TGFbeta-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 TGFbeta 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 TGFbeta-induced apoptosis is ROS-dependent and is a mechanism of dysregulated growth in the chronically inflamed liver.
Comment in
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The cirrhotic hepatocyte: navigating between Scylla and Charybdis.J Hepatol. 2004 Jun;40(6):1027-9. doi: 10.1016/j.jhep.2004.04.007. J Hepatol. 2004. PMID: 15158346 No abstract available.
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