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Title: Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation

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. - Highlights: • Fenofibrate induces cell death by increasing ROS production. • The underlying defense mechanism against this effect is unknown. • Fenofibrate induces autophagy-dependent Keap1 degradation and Nrf2 activation. • This process is p62-dependent; lack ofmore » p62 enhanced fenofibrate-mediated apoptosis. • p62 plays a crucial role in preventing fenofibrate-induced cell death.« less

Authors:
 [1];  [2];  [1]
  1. Severance Biomedical Science Institute (Korea, Republic of)
  2. Department of Life Science and Ewha Research Center for Systems Biology (Korea, Republic of)
Publication Date:
OSTI Identifier:
22458561
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 465; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; CYSTEINE; ECR HEATING; FIBROBLASTS; GLUTATHIONE; HEME; LIVER; MICE; OXIDATION; OXYGEN; RECEPTORS; STRESSES

Citation Formats

Park, Jeong Su, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Kang, Dong Hoon, The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, Lee, Da Hyun, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Bae, Soo Han, E-mail: soohanbae@yuhs.ac, and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752. Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.08.056.
Park, Jeong Su, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Kang, Dong Hoon, The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, Lee, Da Hyun, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Bae, Soo Han, E-mail: soohanbae@yuhs.ac, & Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752. Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation. United States. https://doi.org/10.1016/J.BBRC.2015.08.056
Park, Jeong Su, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Kang, Dong Hoon, The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750, Lee, Da Hyun, Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Bae, Soo Han, E-mail: soohanbae@yuhs.ac, and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752. 2015. "Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation". United States. https://doi.org/10.1016/J.BBRC.2015.08.056.
@article{osti_22458561,
title = {Fenofibrate activates Nrf2 through p62-dependent Keap1 degradation},
author = {Park, Jeong Su and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 and Kang, Dong Hoon and The Research Center for Cell Homeostasis, Ewha Womans University, Seoul 127-750 and Lee, Da Hyun and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 and Bae, Soo Han, E-mail: soohanbae@yuhs.ac and Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752},
abstractNote = {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. - Highlights: • Fenofibrate induces cell death by increasing ROS production. • The underlying defense mechanism against this effect is unknown. • Fenofibrate induces autophagy-dependent Keap1 degradation and Nrf2 activation. • This process is p62-dependent; lack of p62 enhanced fenofibrate-mediated apoptosis. • p62 plays a crucial role in preventing fenofibrate-induced cell death.},
doi = {10.1016/J.BBRC.2015.08.056},
url = {https://www.osti.gov/biblio/22458561}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 465,
place = {United States},
year = {Fri Sep 25 00:00:00 EDT 2015},
month = {Fri Sep 25 00:00:00 EDT 2015}
}