Concerted action of p62 and Nrf2 protects cells from palmitic acid-induced lipotoxicity

Biochemical and Biophysical Research Communications
Jeong Su ParkSoo Han Bae

Abstract

Nonalcoholic fatty liver disease (NAFLD), frequently associated with obesity and diabetes mellitus, is caused by the accumulation of excess fatty acids within liver cells. Palmitic acid (PA), a common saturated fatty acid found in mammals, induces the generation of reactive oxygen species (ROS) and elicits apoptotic cell death, known as lipotoxicity. However, protective mechanisms against PA-induced lipotoxicity have not been elucidated. In this study, we aimed to clarify the role of p62, an adapter protein in the autophagic process, as well as the nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway, in protecting cells from PA-induced lipotoxicity. The Nrf2-Keap1 pathway is essential for the protection of cells from oxidative stress. p62 enhances its binding to Keap1 and leads to Nrf2 activation. Here, we show that PA potentiates Keap1 degradation and thereby activates the transcription of Nrf2 target genes partially through autophagy. Furthermore, this PA-mediated Keap1 degradation depends on p62. Correspondingly, a lack of p62 attenuates the PA-mediated Nrf2 activation and increases the susceptibility of cells to oxidative stress. These results indicate that p62 plays an imp...Continue Reading

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Citations

Feb 4, 2019·Journal of Neuroendocrinology·Delia RamírezMercedes Lasaga
Feb 28, 2020·Evidence-based Complementary and Alternative Medicine : ECAM·Pingping WuLi Xu
Nov 7, 2018·Journal of Cell Science·Pablo Sánchez-Martín, Masaaki Komatsu
Dec 19, 2016·International Journal of Cardiology·Alessandra QuercioliFabrizio Montecucco
May 4, 2021·Frontiers in Cell and Developmental Biology·Vitor de Miranda RamosPamela A Kakimoto

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