2. Academic Validation
  3. Hesperetin Protects from Palmitic-Acid-Induced Lipotoxicity through the Inhibition of Glutaminolysis, mTORC1 Signaling, and Limited Apoptosis

Hesperetin Protects from Palmitic-Acid-Induced Lipotoxicity through the Inhibition of Glutaminolysis, mTORC1 Signaling, and Limited Apoptosis

  • J Agric Food Chem. 2025 Sep 3;73(35):21932-21946. doi: 10.1021/acs.jafc.5c05570.
Wan Li 1 2,  Zhengnan Cai 1 2,  Florian Schindler 1 3,  Martin Brenner 1 2 3,  Christian Winter 4,  Bianca Stiller 5 6,  Petra Heffeter 5,  Wolfram Weckwerth 1 7 8
Affiliations

Affiliations

  • 1 Molecular Systems Biology (MOSYS), Department of Functional and Evolutionary Ecology, University of Vienna, Vienna 1030, Austria.
  • 2 Vienna Doctoral School of Ecology and Evolution, University of Vienna, Vienna 1030, Austria.
  • 3 Vienna Doctoral School of Pharmaceutical, Nutritional and Sports Sciences, University of Vienna, Vienna 1090, Austria.
  • 4 Marine Biology, Department of Functional and Evolutionary Ecology, University of Vienna, Vienna 1030, Austria.
  • 5 Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Vienna 1090, Austria.
  • 6 Research Cluster "Translational Cancer Therapy Research", University of Vienna, Vienna 1090, Austria.
  • 7 Vienna Metabolomics Center (VIME), University of Vienna, Vienna 1030, Austria.
  • 8 Health in Society Research Network, University of Vienna, Vienna 1030, Austria.
PMID: 40838694 DOI: 10.1021/acs.jafc.5c05570
Abstract

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.

Keywords

glutaminolysis; hesperetin; isotope labeling; lipotoxicity; mTORC1.

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