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| Main Authors: | , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of agricultural and food chemistry
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/40838694/ |
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Table of Contents:
- Hesperetin Protects from Palmitic-Acid-Induced Lipotoxicity through the Inhibition of Glutaminolysis, mTORC1 Signaling, and Limited Apoptosis. Li, Wan Cai, Zhengnan Schindler, Florian Brenner, Martin Winter, Christian Stiller, Bianca Heffeter, Petra Weckwerth, Wolfram Hesperidin Apoptosis Mechanistic Target of Rapamycin Complex 1 Signal Transduction Humans Palmitic Acid Glutamine Protective Agents Autophagy Non-alcoholic Fatty Liver Disease Palmitic acid-induced lipotoxicity contributes to the development of nonalcoholic fatty liver disease (NAFLD). Hesperetin has been reported to alleviate oxidative stress, inflammation, and cell death in NAFLD, while its potential to mitigate palmitic acid-induced lipotoxicity remains unexplored. This study investigates the protective effects of hesperetin on palmitic-acid-stimulated lipotoxicity and elucidates the underlying molecular mechanisms. Our results showed that hesperetin decreased palmitic acid-activated lipotoxicity through inhibition of the intrinsic apoptosis pathway and promotion of autophagic flux. Metabolomics analysis and stable-isotope-tracing data indicated that hesperetin treatment restored the aberrant tricarboxylic acid cycle caused by palmitic acid exposure, accompanied by a decrease in anaplerotic flux from glutamine to α-ketoglutarate. The reduction of α-ketoglutarate resulted in the inhibition of mTORC1 signaling, which in turn activated autophagy and limited apoptosis. Furthermore, hesperetin activated AMPK, which coordinated with mTORC1 to regulate autophagy. Additionally, hesperetin reinstated the activation of AKT and Nrf2, further protecting the cell against the deleterious effects of lipotoxicity. These data highlight the role of glutaminolysis as a survival mechanism for preventing lipotoxicity upon hesperetin treatment.