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.

• Authors: Jeong Su Park, Dong Hoon Kang, Da Hyun Lee, Soo Han Bae
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 465 Issue 3 Pg. 542-7 (Sep 25 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26282199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytoskeletal Proteins
• Heat-Shock Proteins
• Hypolipidemic Agents
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Reactive Oxygen Species
• Sequestosome-1 Protein
• Sqstm1 protein, mouse
• Fenofibrate

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Apoptosis (drug effects)
• Cells, Cultured
• Cytoskeletal Proteins (metabolism)
• Dose-Response Relationship, Drug
• Fenofibrate (administration & dosage)
• Fibroblasts (cytology, drug effects, metabolism)
• Heat-Shock Proteins (metabolism)
• Hypolipidemic Agents (administration & dosage)
• Kelch-Like ECH-Associated Protein 1
• Mice
• NF-E2-Related Factor 2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Sequestosome-1 Protein