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Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder

View ORCID ProfileCarla Perpiñá-Clérigues, Susana Mellado, View ORCID ProfileCristina Galiana-Roselló, María Fernández-Regueras, Miguel Marcos, View ORCID ProfileFrancisco García-García, View ORCID ProfileMaría Pascual
doi: https://doi.org/10.1101/2023.09.12.557479
Carla Perpiñá-Clérigues
1Computational Biomedicine Laboratory, Príncipe Felipe Research Center, 46012 Valencia, Spain
2Department of Physiology, School of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
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  • ORCID record for Carla Perpiñá-Clérigues
Susana Mellado
2Department of Physiology, School of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
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Cristina Galiana-Roselló
3Institute of Molecular Science, University of Valencia, Department of Inorganic Chemistry, 46009, Paterna, Spain
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María Fernández-Regueras
4Hospital Universitario de Burgos, 09006 Burgos, Spain
5Hospital Universitario de Salamanca, 37007 Salamanca, Spain
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Miguel Marcos
6Department of Internal Medicine, University Hospital of Salamanca, University of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
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Francisco García-García
1Computational Biomedicine Laboratory, Príncipe Felipe Research Center, 46012 Valencia, Spain
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  • For correspondence: maria.pascual@uv.es fgarcia@cipf.es
María Pascual
2Department of Physiology, School of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
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  • ORCID record for María Pascual
  • For correspondence: maria.pascual@uv.es fgarcia@cipf.es
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Abstract

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, and the consumption of this substance is considered one of the main causes of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes, however little is known about the role of lipids containing extracellular vesicles (EVs), as regulatory molecules and biomarkers. In this study, a highly sensitive lipidomic strategy is employed to characterize plasma EV lipid species from individuals with AUD, to evaluate differential functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism in the alcohol consumption. Plasma EV lipids from female and male patients with AUD and healthy individuals were analyzed to obtain lipid differential abundance, as well as biological interpretation of LINEX2 lipidomics data, evaluating enzymatic dysregulation through an enrichment algorithm. Our results showed for the first time that females with AUD exhibit greater substrate-product changes in LPC and PC lipids, as well as phospholipases and acyltransferases activity, potentially linked to cancer progression and neuroinflammation. Conversely, males with AUD showed dysregulation in Cer and SM lipid, involving sphingomyelinases, sphingomyelin phosphodiesterase, and sphingomyelin synthase, which could be related with hepatotoxicity. Notably, females with AUD showed LION-terms associated with “positive intrinsic curvature”, while males exhibited “negative intrinsic curvature, contributing to vesicle fusion processes. These methodological developments allow a better understanding of lipid metabolism and its regulatory mechanisms, which contributes not only to identify novel lipid targets, but also the discovery of sex-specific clinical biomarkers in the AUD.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://bioinfo.cipf.es/sal-chronics

  • Abbreviations

    ASM
    Acid Sphingomyelinase
    ENPP7
    Ectonucleotide pyrophosphatase/phosphodiesterase family member 7
    LPCAT 1/3/4
    Lysophosphatidylcholine Acyltransferases 1/3/4
    PLA2
    Phospholipase A2
    SMPD
    Sphingomyelin Phosphodiesterase
    SGMS1
    Sphingomyelin Synthase 1
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    Posted September 14, 2023.
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    Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder
    Carla Perpiñá-Clérigues, Susana Mellado, Cristina Galiana-Roselló, María Fernández-Regueras, Miguel Marcos, Francisco García-García, María Pascual
    bioRxiv 2023.09.12.557479; doi: https://doi.org/10.1101/2023.09.12.557479
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    Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder
    Carla Perpiñá-Clérigues, Susana Mellado, Cristina Galiana-Roselló, María Fernández-Regueras, Miguel Marcos, Francisco García-García, María Pascual
    bioRxiv 2023.09.12.557479; doi: https://doi.org/10.1101/2023.09.12.557479

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