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Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation

Title
Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation
Authors
Park J.S.Kang D.H.Lee da H.Bae S.H.
Ewha Authors
강동훈
SCOPUS Author ID
강동훈scopus
Issue Date
2015
Journal Title
Biochemical and biophysical research communications
ISSN
1090-2104JCR Link
Citation
vol. 465, no. 3, pp. 542 - 547
Keywords
AutophagyFenofibrateKeap1Nrf2p62PPARα
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Peroxisome proliferator-activated receptor α (PPARα) activates the β-oxidation of fatty acids in the liver. Fenofibrate is a potent agonist of PPARα and is used in the treatment of hyperlipidemia. Fenofibrate treatment often induces the production of intracellular reactive oxygen species (ROS), leading to cell death. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is an essential component of the defense mechanism against oxidative stress. However, the molecular mechanism underlying the regulation of the Nrf2-Keap1 pathway in fenofibrate-induced cell death is not known. In this study, we demonstrated that fenofibrate induces Keap1 degradation and Nrf2 activation. This fenofibrate-mediated Keap1 degradation is partly dependent on autophagy. Furthermore, fenofibrate-induced Keap1 degradation followed by Nrf2 activation is mainly mediated by p62, which functions as an adaptor protein in the autophagic pathway. Consistent with these findings, ablation of p62 increased fenofibrate-mediated apoptotic cell death associated with ROS accumulation. These results strongly suggest that p62 plays a crucial role in preventing fenofibrate-induced cell death. Copyright © 2015 Elsevier Inc. All rights reserved.
DOI
10.1016/j.bbrc.2015.08.056
Appears in Collections:
연구기관 > 세포항상성연구센터 > Journal papers
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