Abstract
Background/objectives Coronavirus disease 2019 (COVID-19) patients exhibit 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.
Methods A Spike cell line in HEK293 was generated 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.
Results As compared with controls, the Spike cells showed a significant increase in lipid depositions on cell membranes as well as dysregulation of expression of a panel of molecules involved 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.
Conclusions 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.
Highlights
The Spike protein increases lipid deposition in host cell membranes
The Spike protein impairs lipid metabolic and autophagic pathways
The Spike protein exaggerates PA-induced lipotoxicity in host cells via ferroptosis
Nrf2 inhibitor Trigonelline can mitigate the Spike protein-induced necrosis
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of Interest: Disclosure: None Declared
Disclaimer Any views expressed here represent personal opinion and do not necessarily reflect those of the U.S. Department of Health and Human Services or the United States federal government.
Prior Publication: None of the material in this manuscript has been published or is under consideration for publication elsewhere, including the Internet.
Funding statement: This work was supported by grants from the National Institutes of Health (AR073172 and NIH COBRE (P20GM109091) pilot study to W.T., NSF EPSCoR (OIA1736150), HL131667 to T.C.).
