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1.
Cells ; 11(12)2022 06 14.
Article in English | MEDLINE | ID: covidwho-1896808

ABSTRACT

Coronavirus disease 2019 (COVID-19) patients show lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. We generated a Spike cell line in HEK293 using the pcDNA vector carrying the Spike gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. As compared with controls, the Spike cells showed a significant increase in lipid depositions in cell membranes as well as dysregulation of expression of a panel of molecules involving lipid metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis, which could be attenuated by the Nrf2 inhibitor trigonelline. We conclude that the Spike protein impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments.


Subject(s)
COVID-19 , SARS-CoV-2 , GA-Binding Protein Transcription Factor/metabolism , HEK293 Cells , Humans , Lipid Metabolism , NF-E2-Related Factor 2/metabolism , Necrosis , Palmitic Acid/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
2.
Int J Mol Sci ; 22(13)2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1295858

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 2.7 million lives globally. Obesity has been associated with increased severity and mortality of COVID-19. However, the molecular mechanisms by which obesity exacerbates COVID-19 pathologies are not well-defined. The levels of free fatty acids (FFAs) are elevated in obese subjects. This study was therefore designed to examine how excess levels of different FFAs may affect the progression of COVID-19. Biological molecules associated with palmitic acid (PA) and COVID-19 were retrieved from QIAGEN Knowledge Base, and Ingenuity Pathway Analysis tools were used to analyze these datasets and explore the potential pathways affected by different FFAs. Our study found that one of the top 10 canonical pathways affected by PA was the coronavirus pathogenesis pathway, mediated by key inflammatory mediators, including PTGS2; cytokines, including IL1ß and IL6; chemokines, including CCL2 and CCL5; transcription factors, including NFκB; translation regulators, including EEF1A1; and apoptotic mediators, including BAX. In contrast, n-3 fatty acids may attenuate PA's activation of the coronavirus pathogenesis pathway by inhibiting the activity of such mediators as IL1ß, CCL2, PTGS2, and BAX. Furthermore, PA may modulate the expression of ACE2, the main cell surface receptor for the SARS-CoV-2 spike protein.


Subject(s)
COVID-19/metabolism , Fatty Acids, Nonesterified/metabolism , Obesity/metabolism , Palmitic Acid/metabolism , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/epidemiology , COVID-19/pathology , Chemokines/metabolism , Computational Biology/methods , Cytokines/metabolism , Databases, Factual , Fatty Acids, Nonesterified/blood , Humans , Inflammation Mediators/metabolism , Obesity/pathology , Pandemics , SARS-CoV-2/isolation & purification
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