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

  1. Vi Nguyen
  2. Yuping Zhang
  3. Chao Gao
  4. Xiaoling Cao
  5. Yan Tian
  6. Wayne Carver
  7. Hippokratis Kiaris
  8. Taixing Cui
  9. Wenbin Tan
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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

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