Integrated Analysis of Sphingolipid Metabolism and Extracellular Particle Composition in the Context of a Hight-Fat-Diet: Implications for Lipoproteins, Vesicle Biogenesis, and the Role in Macrophage Response to COVID-19

• Grant number: 24/03414-5
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2024
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Carlos Arterio Sorgi
• Grantee: Carlos Arterio Sorgi
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Ana Paula Morais Fernandes ; Ana Paula Ramos ; Cristina Ribeiro de Barros Cardoso ; Eurico de Arruda Neto ; Fausto Bruno dos Reis Almeida ; Lúcia Helena Faccioli ; Mariana Kiomy Osako ; Pietro Ciancaglini ; Ronaldo Bragança Martins Júnior
• Associated research grant(s): 24/19283-7 - Scientific cooperation for the investigation of the role of endoproteases and their substrates in lipid metabolic regulation and their implications for obesity and hepatic steatosis, AP.R SPRINT
• Associated scholarship(s): 25/03148-6 - Hepatic Lipid Alterations Mediated by MMP-12 Activity: Implications in Sexual Dimorphism of Metabolic Steatohepatitis in High-fat Diet, BP.DR; 24/22462-0 - Space radiation effects on lipid composition of plasma and extracellular vesicles: lipidomic applications in astronaut physiology, BP.MS; 24/22891-9 - Purification and sphingolipidomic analysis of lipid particles from human plasma, BP.IC

Abstract

Sphingolipids (SL) are structurally and functionally diverse molecules with important physiological functions, found associated with cell membranes, plasma lipoproteins, or extracellular vesicles (EV). Concentrations of SL are altered in various metabolic disorders such as obesity, implicating the regulation of inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance. Obesity has been considered a comorbidity factor for severe COVID-19 caused by the SARS-CoV-2 virus, although the mechanisms related to this condition are still poorly understood. In this context, SL, which is modified in high-fat diets (HFD), has been described as critical factors in the regulation of viral replication and innate immune response. Indeed, our research group, using quantitative sphingolipidomic technology, has demonstrated SL species as clinical and inflammatory markers associated with COVID-19 in patients. Therefore, understanding the metabolic variations of SL and their influence on the response to SARS-CoV-2 infection will be crucial for the development of effective therapies and preventing "long COVID." In this project, we propose an integrated approach to evaluating SL metabolism and its transport/composition in lipoproteins and EV, using an experimental metabolic condition of HFD. Additionally, we will explore the influence of SL-carrying extracellular particles on macrophage response to COVID-19. Our strategies include: i) murine experimental model - purification and characterization of lipoproteins (HDL, LDL, VLDL), EV, and plasma exosomes from animals on HFD and/or treated with inhibitors of SL and cholesterol metabolism enzymes; ii) in vitro cell culture model - inflammatory and antiviral response of macrophages to SARS-CoV-2 infection, and/or incubation with extracellular lipid particles; iii) bioanalytics - determining SL content in various lipid particles through quantitative mass spectrometry (LC-MS/MS); iv) translational human model - reanalyzing lipidomic and lipid profile data from COVID-19 patients' plasma, stratifying by body mass index (BMI) and gender. Thus, this study will advance understanding of SL metabolism modulation in comorbidity conditions and pathophysiology, as well as potential therapeutic intervention strategies and the use of biomarkers in COVID-19. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DA SILVA-NETO, PEDRO V.; DE CARVALHO, JONATAN C. S.; TORO, DIANA M.; OLIVEIRA, BIANCA T. M.; COMINAL, JUCARA G.; CASTRO, RICARDO C.; ALMEIDA, MARIA A.; PRADO, CIBELE M.; ARRUDA, EURICO; FRANTZ, FABIANI G.; et al. TREM-1-Linked Inflammatory Cargo in SARS-CoV-2-Stimulated Macrophage Extracellular Vesicles Drives Cellular Senescence and Impairs Antibacterial Defense. Viruses-Basel, v. 17, n. 5, p. 20-pg., 2025-04-24. (23/07776-6, 24/03414-5, 21/04590-3, 22/07287-2)

VILELA, ADRIANA F. L.; PATRICIO, MIGUEL R.; NOBRE-AZEVEDO, PEDRO; DE CARVALHO, JONATAN C. S.; DEFELIPPO-FELIPPE, THIAGO, V; PONTES, NATHAN N. H.; RODRIGUES, DANIEL L.; OLIVEIRA, BIANCA T. M.; DA SILVA-NETO, PEDRO V.; NARDINI, VIVIANI; et al. Enhanced lipidomics workflows for plasma and extracellular vesicles through advanced liquid chromatography-tandem mass spectrometry integrated. Talanta, v. 291, p. 13-pg., 2025-03-07. (22/07287-2, 24/03414-5, 21/04590-3)

FELIPPE, THIAGO V. D.; TORO, DIANA M.; DE CARVALHO, JONATAN C. S.; NOBRE-AZEVEDO, PEDRO; RODRIGUES, LUIZ F. M.; OLIVEIRA, BIANCA T. M.; DA SILVA-NETO, PEDRO V.; VILELA, ADRIANA F. L.; ALMEIDA, FAUSTO; FACCIOLI, LUCIA H.; et al. High-resolution targeted mass spectrometry for comprehensive quantification of sphingolipids: clinical applications and characterization of extracellular vesicles. Analytical Biochemistry, v. 698, p. 12-pg., 2024-12-04. (24/03414-5, 21/04590-3, 23/07776-6, 14/07125-6, 20/05207-6, 15/00658-1)