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

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.

Antioxidant Activity of Hemp (Cannabis sativa L.) Seed Oil in Drosophila melanogaster Larvae under Non-Stress and H2O2-Induced Oxidative Stress Conditions

“…In mammalian cells, α-linoleic acid is converted to conjugated ω-3 isomers (DHA, EPA, and docosapentaenoic acid-DPA-22:5n), while linoleic acid via γ-linolenic acid is metabolized to arachidonic acid and eicosadienoic acid (20:2n-6) through the other pathway [77]. DHA and EPA can activate the Keap1/Nrf2 signaling pathway, the major route triggering antioxidant cell response, via stimulation of Nrf2 transcription factor [78,79]. An oxidized metabolite of linoleic acid (12,13-epoxy-9-keto-10(trans)-octadecenoic acid (EKODE)) initiated antioxidant response in neuroblastoma cells and cerebrocortical neurons via activation of the antioxidant response element (ARE), the expression of which is governed by the Nrf2 transcription factor [78].…”

Early Life Intervention Using Probiotic Clostridium butyricum Improves Intestinal Development, Immune Response, and Gut Microbiota in Large Yellow Croaker (Larimichthys crocea) Larvae

“…Large yellow croaker ( Larimichthys crocea ) is an economic important marine fish species in south China ( 18 ). Similarly to most marine fish species, large yellow croaker larvae had an undifferentiated and undeveloped gut and accessory organs ( 19 ).…”

A systems pharmacology approach to identify the autophagy-inducing effects of Traditional Persian medicinal plants

“…Also, the family, major chemical compositions 63 , parts that were used and their applications in TPM 64 were reviewed in Supplementary Table S4 online. Review of modern academic literature confirmed that these herbs contain many compounds (63 out of 1078) that may exert anti-aging effects by inducting autophagy process, through targeting several signaling pathways 65 – 131 .…”

“…Furthermore, the highest percentage of fatty acid in Juglans regia L. corresponds to linoleic acid, oleic acid, and palmitic acid. The effects of these phytochemicals in inducing autophagy were documented by different research groups 84 , 96 , 131 , 135 .…”