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Broncel, M. Lipids in SARS-CoV-2 Infection. Encyclopedia. Available online: https://encyclopedia.pub/entry/10392 (accessed on 23 April 2024).
Broncel M. Lipids in SARS-CoV-2 Infection. Encyclopedia. Available at: https://encyclopedia.pub/entry/10392. Accessed April 23, 2024.
Broncel, Marlena. "Lipids in SARS-CoV-2 Infection" Encyclopedia, https://encyclopedia.pub/entry/10392 (accessed April 23, 2024).
Broncel, M. (2021, June 01). Lipids in SARS-CoV-2 Infection. In Encyclopedia. https://encyclopedia.pub/entry/10392
Broncel, Marlena. "Lipids in SARS-CoV-2 Infection." Encyclopedia. Web. 01 June, 2021.
Lipids in SARS-CoV-2 Infection
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This entry is adapted from the peer-reviewed paper 10.3390/ijms22084177

Being major components of cellular and viral membranes, lipids are undoubtedly involved in viral infections. Membrane/lipid rafts, i.e., cholesterol-rich subdomains of plasma membranes, are crucial elements for membrane fusion and endocytosis.

statins COVID-19 SARS-CoV-2 macrophages activation syndrome (MAS) main protease (Mpro)

1. Introduction

SARS-CoV-2 is a novel coronavirus, and one responsible for the COVID-19 pandemic. The first official reports from Wuhan City, China about numerous cases of acute, severe respiratory syndrome appeared in December 2019, and the coronavirus itself was isolated in January 2020. The rapid spread of the coronavirus around the world forced the WHO to declare a pandemic on 11 March 2020 [1].

Infection with new coronavirus is particularly dangerous for the elderly and for people with cardiovascular disease, obesity, diabetes, chronic respiratory disease, cancer, or decreased immunity [2]. The presence of such comorbidities requires the use of different drugs, and these can affect the response to viral infections in a number of ways. A good example is the use of statins, which are commonly prescribed for high-risk patients worldwide because of their beneficial effect on cardiovascular events [3].

Recent studies indicate that the use of statins lowered mortality by 42% in hospitalized patients with COVID-19 (aHR = 0.58 with (0.43–0.8) 95% CI; p = 0.01); they were also associated with a 20% lower risk of acute respiratory distress syndrome (ARDS) (IRR = 0.80 with (0.67–0.96) 95% CI; p = 0.016) and 49% lower risk of mechanical ventilation (aHR = 0.51 with (0.34–0.78) 95% CI; p = 0.02). Interestingly, statin users were significantly older (66.0 vs. 57.0 years of age, p < 0.001), and were more likely to demonstrate comorbidities including hypertension (81.5% vs. 30.3% p < 0.001), diabetes (34.0% vs. 14.6% p < 0.001), coronary heart disease (36.3% vs. 5.7% p < 0.001), cerebrovascular disease (8.8% vs. 2.3% p < 0.001) compared to non-users [4]. A meta-analysis by Kow et al. including 8990 COVID-19 patients found statins reduce the risk of fatal or severe disease by 30% [5]. It should be emphasized that most of the studies concerned the chronic use of statins prior to SARS-CoV-2 infection—there is still insufficient evidence of the benefits of initiating such therapy de novo in COVID-19.

These results may be caused by the pleiotropic activity of statins, and recent studies suggest various mechanisms that may directly affect SARS-CoV-2 endocytosis (ACE2), replication (main protease and RNA polymerase) or indirect mechanisms unrelated to coronavirus infection, such as e.g., anti-inflammatory, anti-coagulant effects or endothelial function improvement [6][7][8][9][10][11]. In addition, it is very likely that the direct effect on the ACE2 receptor could be of particular importance for the new British coronavirus strain, possibly due to the stronger interaction between the spike protein and the ACE2 receptor [12].

Despite the benefits of this therapy, statin use is associated with a number of side effects, including myopathies, elevated hepatic enzymes and increased risk of diabetes. In addition, some comorbidities of COVID-19 patients, such as nephropathy, diabetes or multiorgan failure, may also affect the efficiency and safety of this therapy [13]. However, Xiao-Jying et al. report that statin use in hospitalised COVID-19 patients was not associated with the increase of creatinine kinase (CK > upper limit of normal ULN aHR 0.97 (0.8–1.17) p = 0.715) or alanine transaminase (ALT > 3ULN aHR 0.98 (0.76–1.26) p = 0.852) [4].

2. Lipids in SARS-CoV-2 Infection

Being major components of cellular and viral membranes, lipids are undoubtedly involved in viral infections. Membrane/lipid rafts, i.e., cholesterol-rich subdomains of plasma membranes, are crucial elements for membrane fusion and endocytosis. An in vitro study found ApoE-mediated cholesterol influx to cause ACE2 translocation to lipid rafts, and depletion of cholesterol with methyl-beta-cyclodextrin (MβCD) reduced the ACE2 receptor localization with lipid rafts by 70% [14]. Lipids not only facilitate membrane fusion, enabling viral cell entry, but also play crucial roles in viral envelopment, replication and exit, i.e., the further steps of viral invasion [15]. Viruses are able to alter the host lipid metabolism to produce fatty acids for their own use; in previous studies, inhibition of fatty acid synthesis was associated with a significant decrease in viral replication [16]. In addition, cholesterol depletion by pretreatment of Vero E6 cells with MβCD was found to cause a significant decrease in the production of SARS-COV-1 particles by infected cells in vitro; this effect was reversed after cholesterol was added to the cellular medium, indicating that the observed reduction of virus particle release was caused by the loss of cholesterol in the cell membrane [17]. Extracting cholesterol from human embryonic kidney 293T cell membranes with MβCD reduced the entry of retroviruses pseudotyped with the SARS-CoV-2 S proteins (SARS2-PV) by 90% [14].

In addition, metabolomic studies suggest that lipids are strongly associated with the host response to SARS-COV-2 infection. Barberis et al. report that the severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. Down-regulation of glycerophospholipids and upregulation of lysophospholipids, arachidonic and oleic acids was observed in sera of COVID-19 patients, indicating that phospholipase A2 (PLA2) is involved in COVID-19 pathogenesis and progression [18]. The activity of PLA2 stimulates the increase of inflammatory lipid mediators such as prostaglandins, leukotrienes and lysophospholipids; these may also play a crucial role in the regulation of inflammatory response, which can influence the prognosis of COVID-19 patients [19]. Moreover, the inhibition of cytosolic phospholipase A2 (cPLA2) with the use of the low-molecular-weight nonpeptidic inhibitor pyrrolidine-2 (Py-2) blocked the replication of Coronaviridae viruses [20].

Patients with SARS-COV 2 infection experience serum lipid disturbances. Studies have found TC, LDL-C and HDL-C levels to be significantly lower in COVID-19 patients than in uninfected patients. Lipid levels were also correlated with the COVID-19 severity. Patients with median total cholesterol 173 mg/dL (148, 204) tended to demonstrate a mild COVID course, those with 167 mg/dL (138, 197) demonstrated a severe course, while those with 125 mg/dL (95, 162) demonstrated a critical course (p < 0.05). Similarly, for LDL-C, median 91 mg/dL (76, 104) was associated with a mild COVID course, 86 mg/dL (69, 102) with a severe course and 69 mg/dL (48, 81) with a critical course (p < 0.02). For HDL-C, median 50 mg/dL (42, 59) was associated with a mild course, 50 mg/dL (41, 59) with a severe course and 36 mg/dL (29, 43) with a critical course (p < 0.05). For triglicerides, median 150 mg/dL (124, 213) was associated with a mild COVID course, 142 mg/dL (89, 189) with a severe course and 115 mg/dL (88, 186) with a critical course (p < 0.01) [21][22].

Low HDL was suggested to be an independent risk factor for a severe course of COVID-19. COVID-19 patients with low HDL at admission (median, 27 vs. 31 mg/dL, p = 0.032) had nearly a three-fold greater risk of developing a severe course of the disease than those with high HDL-C (HR 2.827, 95% CI 1.190–6.714, p = 0.019). This may be helpful in identifying patients at high risk of critical COVID-19 course who need more intense monitoring [23]. Unfortunately, the authors did not consider lipid lowering therapy in their analyses; however, these studies were performed on a Chinese population, where the use of statins is not common, even in secondary prevention [24].

Association of COVID-19 course and hypolipidemia may be supported by the fact, that SARS-CoV-2 requires lipids for the infection. There is no evidence that statins by lowering lipids may exacerbate COVID-19. On the contrary, in retrospective analysis of 170 hospitalized COVID-19 patients the use of statins prior to admission was associated with reduced risk of severe course of the disease by 70% (adjusted OR 0.29, 95%CI 0.11 to 0.71, p < 0.01) [25]. Statins, as hypolipidemic drugs may decrease the infectivity of SARS-CoV-2 by disrupting lipid rafts and lowering membrane cholesterol levels [26]. However statins are not only associated with lowering lipid levels, they also exert pleiotropic effects such as attenuating inflammation and atherosclerotic plaque stabilization which may be crucial in patients with atherosclerosis and COVID-19 [27]. The issue of atherosclerotic plaque stability should be more investigated in patients with SARS-CoV-2 infection.

References

  1. World Health Organization. Timeline: WHO’s COVID-19 Response. Available online: (accessed on 5 February 2021).
  2. Parohan, M.; Yaghoubi, S.; Seraji, A.; Javanbakht, M.H.; Sarraf, P.; Djalali, M. Risk factors for mortality in patients with Coronavirus disease 2019 (COVID-19) infection: A systematic review and meta-analysis of observational studies. Aging Male 2020, 8, 1–9.
  3. Mach, F.; Baigent, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur. Heart J. 2020, 41, 111–188.
  4. Zhang, X.-J.; Qin, J.-J.; Cheng, X.; Shen, L.; Zhao, Y.-C.; Yuan, Y.; Lei, F.; Chen, M.-M.; Yang, H.; Bai, L.; et al. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020, 32, 176–187.e4.
  5. Kow, C.S.; Hasan, S.S. Meta-analysis of Effect of Statins in Patients with COVID-19. Am. J. Cardiol. 2020, 134, 153–155.
  6. Niedzielski, M.; Broncel, M.; Gorzelak-Pabiś, P.; Woźniak, E. New possible pharmacological targets for statins and ezetimibe. Biomed. Pharmacother. 2020, 129, 110388.
  7. Shin, Y.H.; Min, J.J.; Lee, J.-H.; Kim, E.-H.; Kim, G.E.; Kim, M.H.; Lee, J.J.; Ahn, H.J. The effect of fluvastatin on cardiac fibrosis and angiotensin-converting enzyme-2 expression in glucose-controlled diabetic rat hearts. Hear. Vessel. 2016, 32, 618–627.
  8. Bourgonje, A.R.; Abdulle, A.E.; Timens, W.; Hillebrands, J.; Navis, G.J.; Gordijn, S.J.; Bolling, M.C.; Dijkstra, G.; Voors, A.A.; Osterhaus, A.D.M.E.; et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 ( COVID-19). J. Pathol. 2020, 251, 228–248.
  9. Reiner, Ž.; Hatamipour, M.; Banach, M.; Pirro, M.; Al-Rasadi, K.; Jamialahmadi, T.; Radenkovic, D.; Montecucco, F.; Sahebkar, A. Statins and the COVID-19 main protease: In silico evidence on direct interaction. Arch. Med Sci. 2020, 16, 490–496.
  10. Baby, K.; Maity, S.; Mehta, C.H.; Suresh, A.; Nayak, U.Y.; Nayak, Y. Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19. F1000Research 2020, 9, 1166.
  11. Chansrichavala, P.; Chantharaksri, U.; Sritara, P.; Chaiyaroj, S.C. Atorvastatin attenuates TLR4-mediated NF-κB activation in a MyD88-dependent pathway. Asian Pacific J. Allergy Immunol. 2009, 27, 49–57.
  12. Santos, J.C.; Passos, G.A. The high infectivity of SARS-CoV-2 B.1.1.7 is associated with increased interaction force between Spike-ACE2 caused by the viral N501Y mutation. bioRxiv 2020.
  13. Cariou, B.; Goronflot, T.; Rimbert, A.; Boullu, S.; Le May, C.; Moulin, P.; Pichelin, M.; Potier, L.; Smati, S.; Sultan, A.; et al. Routine use of statins and increased COVID-19 related mortality in inpatients with type 2 diabetes: Results from the CORONADO study. Diabetes Metab. 2021, 47, 101202.
  14. Wang, H.; Yuan, Z.; Pavel, M.A.; Hansen, S. Cholesterol and COVID19 lethality in elderly. bioRxiv 2020, 15, 1–14.
  15. Lorizate, M.; Kräusslich, H.-G. Role of Lipids in Virus Replication. Cold Spring Harb. Perspect. Biol. 2011, 3, a004820.
  16. Sanchez, E.L.; Lagunoff, M. Viral activation of cellular metabolism. Virology 2015, 479-480, 609–618.
  17. Li, G.-M.; Li, Y.-G.; Yamate, M.; Li, S.-M.; Ikuta, K. Lipid rafts play an important role in the early stage of severe acute respiratory syndrome-coronavirus life cycle. Microbes Infect. 2007, 9, 96–102.
  18. Barberis, E.; Timo, S.; Amede, E.; Vanella, V.V.; Puricelli, C.; Cappellano, G.; Raineri, D.; Cittone, M.G.; Rizzi, E.; Pedrinelli, A.R.; et al. Large-Scale Plasma Analysis Revealed New Mechanisms and Molecules Associated with the Host Response to SARS-CoV-2. Int. J. Mol. Sci. 2020, 21, 8623.
  19. Hammock, B.D.; Wang, W.; Gilligan, M.M.; Panigrahy, D. Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)? Am. J. Pathol. 2020, 190, 1782–1788.
  20. Müller, C.; Hardt, M.; Schwudke, D.; Neuman, B.W.; Pleschka, S.; Ziebuhr, J. Inhibition of cytosolic phospholipase A2α impairs an early step of coronavirus replication in cell culture. J. Virol. 2017, 92, JVI.01463-17.
  21. Hu, X.; Chen, D.; Wu, L.; He, G.; Ye, W. Low Serum Cholesterol Level Among Patients with COVID-19 Infection in Wenzhou, China. SSRN Electron. J. 2020.
  22. Wei, X.; Zeng, W.; Su, J.; Wan, H.; Yu, X.; Cao, X.; Tan, W.; Wang, H. Hypolipidemia is associated with the severity of COVID-19. J. Clin. Lipidol. 2020, 14, 297–304.
  23. Wang, G.; Zhang, Q.; Zhao, X.; Dong, H.; Wu, C.; Wu, F.; Yu, B.; Lv, J.; Zhang, S.; Wu, G.; et al. Low high-density lipoprotein level is correlated with the severity of COVID-19 patients: An observational study. Lipids Heal. Dis. 2020, 19, 1–7.
  24. Chen, Y.; Li, L.; Zhang, Q.; Clarke, R.; Chen, J.; Guo, Y.; Bian, Z.; Pan, X.; Peto, R.; Tao, R.; et al. Use of drug treatment for secondary prevention of cardiovascular disease in urban and rural communities of China: China Kadoorie Biobank Study of 0.5million people. Int. J. Cardiol. 2014, 172, 88–95.
  25. Daniels, L.B.; Sitapati, A.M.; Zhang, J.; Zou, J.; Bui, Q.M.; Ren, J.; Longhurst, C.A.; Criqui, M.H.; Messer, K. Relation of Statin Use Prior to Admission to Severity and Recovery Among COVID-19 Inpatients. Am. J. Cardiol. 2020, 136, 149–155.
  26. Abu-Farha, M.; Thanaraj, T.A.; Qaddoumi, M.G.; Hashem, A.; Abubaker, J.; Al-Mulla, F. The Role of Lipid Metabolism in COVID-19 Virus Infection and as a Drug Target. Int. J. Mol. Sci. 2020, 21, 3544.
  27. Ferrari, F.; Santos, R.D. Statins and COVID-19: To Suspend or Not to Suspend? That is the Question! Estatinas e COVID-19: Suspender ou não Suspender? Eis a Questão! Arq. Bras. Cardiol. 2021, 116, 147–152.
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Marlena Broncel
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