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Toxicology. 2014 Feb 28;316:61-70. doi: 10.1016/j.tox.2013.12.007. Epub 2014 Jan 3.

Exploring the effects of tert-butylhydroperoxide induced liver injury using proteomic approach.

Author information

  • 1Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taiwan.
  • 2Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan; Chang Gung University College of Medicine, Taoyuan, Taiwan.
  • 3Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taiwan.
  • 4Department of Colorectal Surgery, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Surgery, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
  • 5Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
  • 6Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taiwan.
  • 7Department of Nursing, Chang Gung University of Science and Technology, Taiwan; Chronic Diseases and Health Promotion Research Center, CGUST, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
  • 8School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan; Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Emergency Medicine, Cathay General Hospital, Taipei 10630, Taiwan.
  • 9Division of Hematology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
  • 10Department of Nursing, Chang Gung University of Science and Technology, Taiwan; Chronic Diseases and Health Promotion Research Center, CGUST, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan. Electronic address: guscsi@gmail.com.

Abstract

Tert-butyl hydroperoxide (t-BHP), an organic lipid hydroperoxide analog, has been demonstrated to exert pro-oxidant effects to evaluate mechanisms involving oxidative stress in hepatocyte cells and rat liver. Herein, we present an investigation of the event of molecular mechanism of t-BHP related acute liver injury. A proteomic approach was used to identify proteins which are differentially expressed in liver cells following t-BHP treatment and the mechanism of its action in apoptotic and endoplasmic reticulum stress pathways. Our results demonstrate that the t-BHP treatment of liver cells increased cell cytoxicity and apoptosis. t-BHP dose-dependent induction of cell apoptosis and stained liver sections relieved the acute rat liver injury were accompanied by sustained phosphorylation of JNK1/2 and p65. In addition, there were 13 differentially displayed proteins between the t-BHP-induced and untreated were assayed and validated in vivo. Furthermore, we demonstrated that t-BHP induced human Chang liver cell viability and apoptosis properties by up-regulating the levels of ETFA (electron transfer flavoprotein subunit alpha). This study demonstrated that there was an increase in the cellular levels of ETFA in the t-BHP induction in viability and apoptosis via the activation of JNK1/2 and NFκB signaling modules. NAC administration and shRNA ETFA conferred resistance to t-BHP-increased ETFA and CHOP expression via IRE1-alpha/TRAF2 complex formation, activation of JNK1/2 and p50. We concluded that the mechanism of t-BHP-induced an apoptosis cascade and endoplasmic reticulum stress in hepatocyte cells by up-regulation of ETFA, providing a new mechanism for liver injury.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

ETFA; IRE1-alpha/TRAF2; JNK1/2; NFκB; ROS; t-BHP

PMID:
24394546
[PubMed - indexed for MEDLINE]
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