The elevated SARS-CoV-2 protein disrupts lipid metabolism resulting in liver, heart and kidney damage

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China in late December 2019 and spread rapidly across the world to eventually cause the ongoing coronavirus 2019 (COVID-19) pandemic. More than two years later, the pathophysiology of COVID-19 is still poorly understood.

New study published on prepress server bioRxiv * Describes an aspect of the interaction of the virus with the host in terms of its effect on the lipid metabolism of the host.

Stady: The spike protein of SARS-Cov-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implicating a role for Nrf2. Image credit: Skif_Nomad /

an introduction

SARS-CoV-2 is primarily known as elevated glycoprotein antigen that mediates host cell binding and entry; However, this virus also produces multiple changes in the metabolic pathways of the host cells. Thus, people with diabetes, metabolic syndrome, high cholesterol levels, obesity and high blood pressure are at greater risk of severe COVID-19 outcomes than others.

Some evidence suggests that COVID-19 is associated with cardiovascular complications such as myocardial injury and heart failure, which can be exacerbated in the presence of obesity. The authors of the current study previously reported a decrease in total and component lipoproteins in COVID-19 patients, which in turn was associated with severe disease and fatal outcome.

Lipids are essential to the viral life cycle in some viruses, and lipid rafts have been implicated in the replication of SARS viruses. Thus, the current study describes the effects of viral spike protein on host lipid synthesis, turnover, and catabolism.


In contrast to controls, spike protein was associated with impaired lipid metabolism and autophagy processes in the host cell. As a consequence, host cells were more easily affected by lipotoxicity, which was likely due to pathways induced by nuclear factor 2 (Nrf2)-induced activation of erythroid infection.

In cell lines expressing spike protein, there was a greater accumulation of lipids when compared to control cells, especially on the cell membrane. In close association with this change, which indicates impaired lipid metabolism, a number of lipid-related enzymes and proteins were upregulated. At the same time, other markers of autophagy and iron endocytosis also showed altered levels of expression.

Spike protein caused lipid deposition in the host cells.  (A) Generation of a stable spike protein cell line.  Spike protein expression was verified using the marker antibody in Spike cells.  (b) Quantification of Oil Red O staining in mock cells, PCDNA, and Spike with absorbance measurement at 492 nm.  (CE) Histological images showing Oil Red O staining of lipid droplets in mock cells (C), PCDNA (D) and Spike (E).  Nuclear components were counteracted by hematoxylin

Spike protein caused lipid deposition in the host cells. (A) Generation of a stable spike protein cell line. Spike protein expression was verified using the marker antibody in Spike cells. (B) Quantification of Oil Red O staining in mock cells, PCDNA, and Spike with absorbance measurement at 492 nm. (CE) Histological images showing Oil Red O staining of lipid droplets in mock (C), PCDNA (D) and Spike (E) cells. Nuclear components were counteracted by hematoxylin.

The general impression is that the spike protein negatively affected these processes within the host cell. Moreover, with increased palmitic acid (PA) due to abnormal intracellular lipid processing, apoptosis was induced, indicating lipotoxic effects. While this effect was observed in all cell lines where this fatty acid accumulated, the intensity level was improved in the spike-bearing cells.

The effects of such an overload were dependent on both the duration of exposure and the level of PA in the cell. These cells also induced changes in the expression of some genes in response to the lipotoxicity of PA accumulation, within spike-expressing cells but not controls. In this case, the levels of SRB1, ATG7, PTGS2, LC3 I/II and Fth1 were significantly higher compared to the controls.

In obesity, cardiomyocytes exhibit abnormalities of autophagy accompanied by Nrf2-mediated iron deficiency, the latter being key to the changes in transcription observed in adipogenesis. Treatment with the Nrf2 inhibitor Trigonelline (TRG), the ferroptosis inhibitor ferrostatin, and the PI3K inhibitor Wortmannin, reduced the toxic effects of intracellular lipid accumulation that occurred in response to elevated PA that was enhanced in the presence of spike protein.

Similar results were obtained in response to the same process within the cell line that mimics the cardiomyocyte cell line. These observations suggest a role for spike protein in PA accumulation-induced excitotoxicity.


The results of the study demonstrate that the SARS-CoV-2 spike protein has a direct role in exacerbating the toxicity of intracellular lipid accumulation due to the disruption of several lipid pathways in response to viral infection. This provides insight into why obese patients are at greater risk of severe COVID-19 compared to those of normal weight.

Inhibitors of Nrf2, PI3K and ferroptosis were found to reduce this toxic effect, which was observed in the form of altitude-induced necrosis. Interestingly, an alkaloid called TRG, which is found in high levels in coffee, is also an effective inhibitor of lipotoxicity. This represents “A potential and feasible preventive strategy for mitigating obesity-related cardiovascular diseases associated with the emerging corona virus. “

PI3K is a key to autophagy of infected cells during endocytosis and part of the growth factor receptor pathways that drive phosphorylation of viral proteins after SARS-CoV-2 infection. Therefore, PI3K is a suitable target for drugs that fight or prevent COVID-19.

The viral spike protein can disrupt the expression of many PI3Ks in host cells, impairing the natural defense response to SARS-CoV-2. This can be achieved by regulating autophagosome formation while minimizing fusion of autophagosomes with lysosomes. Autophagy subsequently accumulates within the cell, resulting in lipotoxicity.

Because Wortmannin shows the ability to oppose this exaggerated lipid toxicity, this agent, along with other PI3K inhibitors, could be useful in treating COVID-19 patients with elevated blood lipid levels.

Nrf2 is a regulator of more than a thousand genes involved in a range of metabolic and balanced pathways, such as detoxification, protein degradation, and antioxidant defense, as well as iron and lipid metabolism. This broad functional capacity of Nrf2 extends the adaptive capacity of the myocardium and enhances non-cardiac cardiac phenotypes when the normal occurrence of myocardial autophagy is inhibited, as in chronic type 1 diabetes and obesity. This leads to cardiac muscle dysfunction and abnormal remodeling.

The increase in Nrf2 expression in response to the expression of SARS-CoV-2 spike protein was mediated by PA accumulation and the resulting necrosis was suppressed by the Nrf2 inhibitor. Further research will be necessary to elucidate the precise underlying mechanisms of lipid metabolic dysregulation and to determine how impaired Nrf2 signaling causes host cardiac cells in obese COVID-19 patients to experience benign lipotoxicity.

*Important note

bioRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behaviour, or be treated as established information.


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