ω-6 Polyunsaturated fatty acids (linoleic acid) activate both autophagy and antioxidation in a synergistic feedback loop via TOR-dependent and TOR-independent signaling pathways

Cell Death Dis. 2020 Jul 30;11(7):607. doi: 10.1038/s41419-020-02750-0.

Abstract

ω-6 Polyunsaturated fatty acids (PUFAs) are essential fatty acids that participate in macroautophagy (hereafter referred to as autophagy) and the Kelch ECH-associating protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant system in organisms. However, the molecular mechanisms by which ω-6 PUFAs (linoleic acid) regulate autophagy and Keap1-Nrf2 antioxidant system are not completely understood. Therefore, the purposes of this study were to explore the molecular mechanisms by which ω-6 PUFAs (linoleic acid) regulate autophagy and antioxidant system and to investigate the potential relationship between autophagy and antioxidant system through transcriptomic analysis, quantitative real-time polymerase chain reaction (RT-qPCR), western blot analysis, coimmunoprecipitation (Co-IP) and electrophoretic mobility shift assays (EMSAs) in vivo and in vitro. The results of the present study indicated that ω-6 PUFAs in diets induced autophagy but decrease antioxidant ability in vivo. However, the results also provided evidence, for the first time, that ω-6 PUFAs (linoleic acid) induced autophagy and increased antioxidant ability through the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and the AMPK-target of rapamycin (TOR) signaling pathway in hepatocytes in vitro. Interestingly, the findings revealed a ω-6 PUFA-induced synergistic feedback loop between autophagy and antioxidant system, which are connected with each other through the P62 and Keap1 complex. These results suggested that ω-6 PUFAs (linoleic acid) could be useful for activating a synergistic feedback loop between autophagy and antioxidant system and could greatly aid in the prevention and treatment of multiple pathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Antioxidants / pharmacology*
  • Autophagy / drug effects*
  • Base Sequence
  • Dietary Supplements
  • Feedback, Physiological*
  • HEK293 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / ultrastructure
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Linoleic Acid / pharmacology*
  • NF-E2-Related Factor 2 / metabolism
  • Perciformes
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Sequestosome-1 Protein / genetics
  • Sequestosome-1 Protein / metabolism
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Antioxidants
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Linoleic Acid
  • TOR Serine-Threonine Kinases
  • Adenylate Kinase