Primary cirrhotic hepatocytes resist TGFβ-induced apoptosis through a ROS-dependent mechanism

Dalliah Black, Mark A. Bird, Charles M. Samson, Suzanne Lyman, Patty A. Lange, Laura W. Schrum, Ting Qian, J. J. Lemasters, David A. Brenner, Richard A. Rippe, Kevin E. Behrns

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)942-951
Number of pages10
JournalJournal of Hepatology
Volume40
Issue number6
DOIs
StatePublished - Jun 2004

Keywords

  • AdIκB-SR, adenovirus IκB super-repressor
  • AdLuc, adenovirus luciferase
  • Apoptosis
  • CCl, carbon tetrachloride
  • Caspase
  • CyA, cyclosporin A
  • Mitochrondria permeability transition
  • Reactive oxygen species
  • Transforming growth factor beta

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