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The Spike protein of SARS-CoV-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implication for a role of Nrf2

Vi Nguyen, Yuping Zhang, Chao Gao, Xiaoling Cao, Yan Tian, Wayne Carver, Hippokratis Kiaris, Taixing Cui, Wenbin Tan
doi: https://doi.org/10.1101/2022.04.19.488806
Vi Nguyen
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
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Yuping Zhang
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
2Department of General Surgery, The 3rd Xiangya Hospital of Central South University, Changsha, Hunan, China
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Chao Gao
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
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Xiaoling Cao
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
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Yan Tian
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
3Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Wayne Carver
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
4Department of Biomedical Engineering, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
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Hippokratis Kiaris
5Drug Discovery & Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA
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Taixing Cui
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
4Department of Biomedical Engineering, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
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Wenbin Tan
1Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, USA
4Department of Biomedical Engineering, College of Engineering and Computing, University of South Carolina, Columbia, South Carolina, USA
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  • For correspondence: wenbin.tan@uscmed.sc.edu
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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.).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 19, 2022.
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The Spike protein of SARS-CoV-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implication for a role of Nrf2
Vi Nguyen, Yuping Zhang, Chao Gao, Xiaoling Cao, Yan Tian, Wayne Carver, Hippokratis Kiaris, Taixing Cui, Wenbin Tan
bioRxiv 2022.04.19.488806; doi: https://doi.org/10.1101/2022.04.19.488806
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The Spike protein of SARS-CoV-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implication for a role of Nrf2
Vi Nguyen, Yuping Zhang, Chao Gao, Xiaoling Cao, Yan Tian, Wayne Carver, Hippokratis Kiaris, Taixing Cui, Wenbin Tan
bioRxiv 2022.04.19.488806; doi: https://doi.org/10.1101/2022.04.19.488806

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