COVID-19-associated dyslipidemia: the role of lipid and fatty acids in the pathogenesis of SARS-CoV-2 infection

   Introduction. The COVID-19 pandemic is a global public health problem. In COVID-19, systemic inflammation is accompanied by a “cytokine storm”, hypercoagulability, and generalized vasculitis, and new evidence suggests that lipid transportation disorders may exacerbate the course of the disease.

   Aim. Discussion of the role of lipids, fatty acids, and various cascade molecular pathways in the pathogenesis of COVID-19-associated dyslipidemia.

   Results. When conducting a systematic analysis of the scientific literature in the PubMed database, we concluded the following: lipoproteins, oxidized forms of phospholipids and fatty acids can lead to organ damage due to hyperactivation of scavenger of the innate immune response. Thus, restoring lipoprotein function with agents that increase apolipoprotein A-I levels or blocking the relevant scavenger receptors with neutralizing antibodies may be effective in the treatment of COVID-19. The key role of lipoprotein-transported omega-3 fatty acids in the production of specialized proreactive mediators has been demonstrated, and activation of the leukotriene pathway has been shown to be associated with the severity of COVID-19.

   Conclusion. A growing number of scientific studies indicates that lipid and fatty acids have both positive and negative effects in SARS-CoV-2 infection. Additional studies or preclinical models evaluating the eicosanoid profile in patients with COVID-19 will provide new insights into the interaction of the coronavirus with “the host” and the regulation of the inflammatory response.

1. Wang C., Horby P. W., Hayden F. G., Gao G. F. A novel coronavirus outbreak of global health concern // Lancet. 2020. Vol. 395, Iss. 10223. Р. 470–473. https://doi.org/10.1016/S0140-6736(20)30185-9

2. Gualdoni G. A., Mayer K. A., Kapsch A. M. Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication // Proc. Natl Acad. Sci. USA. 2018. Iss. 115, № 30. Р. 7158–7165. https://doi.org/10.1073/pnas.1800525115

3. Yuan S., Chu H., Chan J. F., Ye Z. W., Wen L., Yan B., Lai P. M., Tee K. M., Huang J., Chen D., Li C., Zhao X., Yang D., Chiu M. C., Yip C., Poon V. K., Chan C. C., Sze K. H., Zhou J., Chan I. H., Yuen K. Y. SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target // Nat. Commun. 2019. Vol. 10, Iss. 1. Article number: 120. https://doi.org/10.1038/s41467-018-08015-x

4. Ketter E., Randall G. Virus Impact on Lipids and Membranes // Annu. Rev. Virol. 2019. Vol. 6, Iss. 1. Р. 319–340. https://doi.org/10.1146/annurev-virology-092818-015748

5. Pattnaik G. P., Chakraborty H. Cholesterol: A key player in membrane fusion that modulates the efficacy of fusion inhibitor peptides // Vitam. Horm. 2021. Vol. 117. Р. 133–155. https://doi.org/10.1016/bs.vh.2021.06.003

6. Fernández-Oliva A., Ortega-González P., Risco C. Targeting host lipid flows: Exploring new antiviral and antibiotic strategies // Cell. Microbiol. 2019. Vol. 21, Iss. 3. Article number: 12996. https://doi.org/10.1111/cmi.12996

7. Shen B., Yi X., Sun Y., Bi X., Du J., Zhang C., Quan S., Zhang F., Sun R., Qian L., Ge W., Liu W., Liang S., Chen H., Zhang Y., Li J., Xu J., He Z., Chen B., Wang J., Yan H., Zheng Y., Wang D., Zhu J., Kong Z., Kang Z., Liang X., Ding X., Ruan G., Xiang N., Cai X., Gao H., Li L., Li S., Xiao Q., Lu T., Zhu Y., Liu H., Chen H., Guo T. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera // Cell. 2020. Vol. 9, Iss. 182. Р. 59–72. https://doi.org/10.1016/j.cell.2020.05.032

8. Hu X., Chen D., Wu L., He G., Ye W. Low serum cholesterol level among patients with COVID‐19 infection in Wenzhou // Lancet. 2020. Vol. 29, Iss. 342. Р. 1167–1173. https://doi.org/10.2139/ssrn.3544826

9. Wei X., Zeng W., Su J. Hypolipidemia is associated with the severity of COVID-19 // J. Clin. Lipidol. 2020. Vol. 14, Iss. 14. Р. 297–304. https://doi.org/10.1016/j.jacl.2020.04.008

10. Huang C., Wang Y., Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China // Lancet. 2020. Vol. 395, Iss.3. Р. 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5

11. Alketbi E. H., Hamdy R., El-Kabalawy A., Juric V., Pignitter M., A. Mosa K., Almehdi A. M., El-Keblawy A. A., Soliman S. Lipid-based therapies against SARS-CoV-2 infection // Rev. Med. Virol. 2021. Vol. 31, Iss. 5. Р. 1–13. https://doi.org/10.1002/rmv.2214

12. Bernhard W. Lung surfactant: Function and composition in the context of development and respiratory physiology // Ann. Anat. 2016. Vol.208, Iss. 4. Р. 146–150. https://doi.org/10.1016/j.aanat.2016.08.003

13. Raschetti R., Centorrino R., Letamendia E., Benachi A., Marfaing-Koka A., De Luca D. Estimation of early life endogenous surfactant pool and CPAP failure in preterm neonates with RDS // Respir. Res. 2019. Vol. 20, Iss.1. Article number: 75. https://doi.org/10.1186/s12931-019-1040-z

14. Agudelo C. W., Samaha G., Garcia-Arcos I. Alveolar lipids in pulmonary disease. A review // Lipids Health Dis. 2020. Vol. 19, Iss. 1. Article number: 122. https://doi.org/10.1186/s12944-020-01278-8

15. Guo H., Huang M., Yuan Q., Wei Y., Gao Y., Mao L., Gu L., Tan Y. W., Zhong Y., Liu D., Sun S. The Important Role of Lipid Raft-Mediated Attachment in the Infection of Cultured Cells by Coronavirus Infectious Bronchitis Virus Beaudette Strain // PloS One. 2017. Vol. 12, Iss. 1. Article number: 170123. https://doi.org/10.1371/journal.pone.0170123

16. Sturley S. L., Rajakumar T., Hammond N., Higaki K., Márka Z., Márka S., Munkacsi A. B. Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity // J. Lipid Res. 2020. Vol. 61, Iss. 7. Р. 972–982. https://doi.org/10.1194/jlr.R120000851

17. Regen S. L. The Origin of Lipid Rafts // Biochemistry. 2020. Vol. 59, Iss. 49. Р. 4617–4621. https://doi.org/10.1021/acs.biochem.0c00851

18. Santos-Beneit F., Raškevičius V., Skeberdis V. A., Bordel S. A metabolic modeling approach reveals promising therapeutic targets and antiviral drugs to combat COVID-19 // Sci. Rep. 2021. Vol. 11, Iss. 1. Article number: 11982. https://doi.org/10.1038/s41598-021-91526-3

19. Wei C., Wan L., Yan Q., Wang X., Zhang J., Yang X., Zhang Y., Fan C., Li D., Deng Y., Sun J., Gong J., Yang X., Wang Y., Wang X., Li J., Yang H., Li H., Zhang Z., Wang R., Du P., Zong Y., Yin F., Zhang W., Wang N., Peng Y., Lin H., Feng J., Qin C., Chen W., Gao Q., Zhang R., Cao Y., Zhong H. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry // Nat. Metab. 2020. Vol. 2, Iss. 12. Р. 1391–1400. https://doi.org/10.1038/s42255-020-00324-0

20. Yang N., Han-Ming S. Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19 // Int. J. Biol. Sci. 2020. Vol. 16, Iss. 10. Р. 1724–1731. https://doi.org/10.7150/ijbs.45498

21. Wolff G., Limpens R. W. A. L., Zevenhoven-Dobbe J. C., Laugks U., Zheng S., de Jong A. W. M., Koning R. I., Agard D. A., Grünewald K., Koster A. J., Snijder E. J., Bárcena M. A molecular pore spans the double membrane of the coronavirus replication organelle // Science. 2020. Vol. 369, Iss. 6509. Р. 1395–1398. https://doi.org/10.1126/science.abd3629

22. Strating J. R., van Kuppeveld F. J. Viral rewiring of cellular lipid metabolism to create membranous replication compartments // Curr. Opin. Cell Biol. 2017. Vol. 47, Iss. 3. Р. 24–33. https://doi.org/10.1016/j.ceb.2017.02.005

23. Zhang Z., He G., Filipowicz N. A., Randall G., Belov G. A., Kopek B. G., Wang X. Host Lipids in Positive-Strand RNA Virus Genome Replication // Front. Microbiol. 2019. Vol. 10. Article number: 286. https://doi.org/10.3389/fmicb.2019.00286

24. 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. 2018. Vol. 92, Iss. 4. Article number: e01463-17. https://doi.org/10.1128/JVI.01463-17

25. Wolff G., Melia C. E., Snijder E. J., Bárcena M. Double-Membrane Vesicles as Platforms for Viral Replication // Trends Microbiol. 2020. Vol. 28, Iss. 12. Р. 1022–1033. https://doi.org/10.1016/j.tim.2020.05.009

26. Deevska G. M., Nikolova-Karakashian M. N. The expanding role of sphingolipids in lipid droplet biogenesis // Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 2017. Vol. 1862, Iss.10 (Pt B). P. 1155–1165. https://doi.org/10.1016/j.bbalip.2017.07.008

27. Dias S. S. G., Soares V. C., Ferreira A. C., Sacramento C. Q., Fintelman-Rodrigues N., Temerozo J. R., Teixeira L., Nunes da Silva M. A., Barreto E., Mattos M., de Freitas C. S., Azevedo-Quintanilha I. G., Manso P. P. A., Miranda M. D., Siqueira M. M., Hottz E. D., Pão C. R. R., Bou-Habib D. C., Barreto-Vieira D. F., Bozza F. A., Souza T. M. L, Bozza P. T. Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators // PLoS Pathog. 2020. Vol. 16, Iss. 12. Article number: 1009127. https://doi.org/10.1371/journal.ppat.1009127

28. Pagliari F., Marafioti M. G., Genard G., Candeloro P., Viglietto G., Seco J., Tirinato L. SsRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection? // Front. Mol. Biosci. 2020. Vol. 7. Article number: 5789641347. https://doi.org/10.3389/fmolb.2020.578964

29. Tizaoui C. Ozone: A Potential Oxidant for COVID-19 Virus (SARS-CoV-2) // Ozone: Science & Engineering. 2020. Vol. 42, Iss. 5. Р. 378–385. https://doi.org/10.1080/01919512.2020.1795614

30. Yan B., Chu H., Yang D., Sze K. H., Lai P. M., Yuan S., Shuai H., Wang Y., Kao R. Y., Chan J. F., Yuen K. Y. Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication // Viruses. 2019. Vol.11, Iss.1. Article number: 73. https://doi.org/10.3390/v11010073

31. Pagliari F., Marafioti M. G., Genard G., Candeloro P., Viglietto G., Seco J., Tirinato L. ssRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection? // Front. Mol. Biosci. 2020. Vol. 7. Article number: 578964. https://doi.org/10.3389/fmolb.2020.578964

32. 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. Vol. 21, Iss. 10. Article number: 3544. https://doi.org/10.3390/ijms21103544

33. Moreau R. A., Nyström L., Whitaker B. D., Winkler-Moser J. K., Baer D. J, Gebauer S. K., Hicks K. B. Phytosterols and their derivatives: Structural diversity, distribution, metabolism, analysis, and health-promoting uses // Prog. Lipid Res. 2018. Vol. 70. Р. 35–61. https://doi.org/10.1016/j.plipres.2018.04.001

34. Yan B., Zou Z., Chu H., Chan G., Tsang J. O., Lai P. M., Yuan S., Yip C. C., Yin F., Kao R. Y., Sze K. H., Lau S. K., Chan J. F., Yuen K. Y. Lipidomic Profiling Reveals Significant Perturbations of Intracellular Lipid Homeostasis in Enterovirus-Infected Cells // Int. J. Mol. Sci. 2019. Vol. 20, Iss. 23. Article number: 5952. https://doi.org/10.3390/ijms20235952

35. Hoxha M. What about COVID-19 and arachidonic acid pathway? // Eur. J. Clin. Pharmacol. 2020. Vol. 76, Iss. 11. Р. 1501–1504. https://doi.org/10.1007/s00228-020-02941-w

36. Hammock B. D., Wang W., Gilligan M. M., Panigrahy D. Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)? // Am. J. Pathol. 2020. Vol. 190, Iss. 9. Р. 1782–1788. https://doi.org/10.1016/j.ajpath.2020.06.010

37. Das U. N. Can Bioactive Lipids Inactivate Coronavirus (COVID-19)? // Arch. Med. Res. 2020. Vol. 51, Iss. 3. Р. 282–286. https://doi.org/10.1016/j.arcmed.2020.03.004

38. Soliman S., Faris M. E., Ratemi Z., Halwani R. Switching Host Metabolism as an Approach to Dampen SARS-CoV-2 Infection // Ann. Nutr. Metab. 2020. Vol. 76, Iss. 5. Р. 297–303. https://doi.org/10.1159/000510508

39. Toelzer C., Gupta K., Yadav S. K. N., Borucu U., Davidson A. D., Kavanagh Williamson M., Shoemark D. K., Garzoni F., Staufer O., Milligan R., Capin J., Mulholland A. J., Spatz J., Fitzgerald D., Berger I., Schaffitzel C. Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein // Science. 2020. Vol. 370, Iss. 6517. Р. 725–730. https://doi.org/10.1126/science.abd3255

40. Iddir M., Brito A., Dingeo G., Fernandez Del Campo S. S., Samouda H, La Frano M. R., Bohn T. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis // Nutrients. 2020. Vol. 12, Iss. 6. Article number: 1562. https://doi.org/10.3390/nu12061562

41. Edser C. Surfactants versus COVID-19 // Focus on Surfactants. 2020. Vol. 2020, Iss. 7. Р. 1–2. https://doi.org/10.1016/j.fos.2020.09.001

42. Ghaffari S., Roshanravan N., Tutunchi H., Ostadrahimi A., Pouraghaei M., Kafil B. Oleoylethanolamide, A Bioactive Lipid Amide, as A Promising Treatment Strategy for Coronavirus / COVID-19 // Arch. Med. Res. 2020. Vol. 51, Iss. 5. Р. 464–467. https://doi.org/10.1016/j.arcmed.2020.04.006

43. Gelfand E. W. Importance of the leukotriene B4-BLT1 and LTB4-BLT2 pathways in asthma // Semin. Immunol. 2017. Vol. 1, Iss. 33. Р. 44–51. https://doi.org/10.1016/j.smim.2017.08.005

44. Gautier-Veyret E., Bäck M., Arnaud C., Belaïdi E., Tamisier R., Lévy P., Arnol N., Perrin M., Pépin J. L., Stanke-Labesque F. Cysteinyl-leukotriene pathway as a new therapeutic target for the treatment of atherosclerosis related to obstructive sleep apnea syndrome // Pharmacol. Res. 2018. Vol. 134, Iss. 7. Р. 311–319. https://doi.org/10.1016/j.phrs.2018.06.014

45. Göbel T., Diehl O., Heering J., Merk D., Angioni C., Wittmann S. K., Buscato E., Kottke R., Weizel L., Schader T., Maier T. J. Zafirlukast is a dual modulator of human soluble epoxide hydrolase and peroxisome proliferator-activated receptor γ // Front. Pharmacol. 2019. Vol. 10, Iss. 4. Р. 263–269. https://doi.org/10.3389/fphar.2019.00263

46. Lazarinis N., Bood J., Gomez C., Kolmert J., Lantz A. S., Gyllfors P., Davis A., Wheelock C. E., Dahlén S. E., Dahlén B. Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor // J. Allergy Clin. Immunol. 2018. Vol. 142, Iss. 4. Р. 1080–1089. https://doi.org/10.1016/j.jaci.2018.02.024

47. Davino-Chiovatto J. E., Oliveira-Junior M. C., MacKenzie B., Santos-Dias A., Almeida-Oliveira A. R., Aquino-Junior J. C., Brito A. A., Rigonato-Oliveira N. C., Damaceno-Rodrigues N. R., Oliveira A. P., Silva A. P. Montelukast, leukotriene inhibitor, reduces LPS-induced acute lung inflammation and human neutrophil activation // Arch. Bronconeumol. 2019. Vol. 55, Iss. 11. Р. 573–580. https://doi.org/10.1016/j.arbres.2019.05.003

48. Le Bel M., Brunet A., Gosselin J. Leukotriene B4, an endogenous stimulator of the innate immune response against pathogens // J. Innate Immun. 2014. Vol. 6, Iss. 2. Р. 159–168. https://doi.org/10.1159/000353694

49. Schwerd T., Twigg S. R., Aschenbrenner D., Manrique S., Miller K. A., Taylor I. B., Capitani M., McGowan S. J., Sweeney E., Weber A., Chen L. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis // J. Exp. Med. 2017. Vol. 214, Iss. 9. Р. 2547–2562. https://doi.org/10.1084/jem.20161810

50. Kong M., Zhang H., Cao X., Mao X., Lu Z. Higher level of neutrophil-to-lymphocyte is associated with severe COVID-19 // Epidemiol. Infect. 2020. Vol. 148. Article number: е139. https://doi.org/10.1017/S0950268820001557

51. Copertino D. C., Duarte R. R., Powell T. R., de Mulder Rougvie M., Nixon D. F. Montelukast drug activity and potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) // J. Med. Virol. 2021. Vol. 93, Iss. 1. Р. 187–189. https://doi.org/10.1002/jmv.26299

52. Brash A. R. Arachidonic acid as a bioactive molecule // J. Clin. Invest. 2018. Vol. 107, Iss. 4. Р. 1339–1345. https://doi.org/10.1172/JCI13210

53. Pompéia C., Lopes L. R., Miyasaka C. K., Procópio J., Sannomiya P., Curi R. Effect of fatty acids on leukocyte function // Braz. J. Med. Biol. Res. 2020. Vol. 33, Iss. 1. Р. 1255–1268. https://doi.org/10.1590/S0100-879X2000001100001

54. Beck R., Bertolino S., Abbot S. E., Aaronson P. I., Smirnov S. V. Modulation of arachidonic acid release and membrane fluidity by albumin in vascular smooth muscle and endothelial cells // Circ. Res. 2018. Vol. 83, Iss. 5. Р. 923–931. https://doi.org/10.1161/01.RES.83.9.923

55. Spencer A. G., Woods J. W., Arakawa T., Singer I. I., Smith W. L. Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by immunoelectron microscopy // J. Biol. Chem. 2018. Vol.273, Iss. 25. Р. 9886–9893. https://doi.org/10.1074/jbc.273.16.9886

56. Robb C. T., Goepp M., Rossi A. G., Yao C. Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19 // Br. J. Pharmacol. 2020. Vol. 177, Iss. 21, Р. 4899–4920. https://doi.org/10.1111/bph.15206

57. Fitz Gerald G. A. Misguided drug advice for COVID-19 // Science. 2020. Vol. 80, Iss. 367. Article number: 1434. https://doi.org/10.1126/science.abb8034

58. Savard M., Bélanger C., Tremblay M. J., Dumais N., Flamand L., Borgeat P., Gosselin J. EBV suppresses prosta-glandin e 2 biosynthesis in human monocytes // J. Immunol. 2019. Vol. 164, Iss. 2. Р. 6467–6473. https://doi.org/10.4049/jimmunol.164.12.6467

59. Janelle M. E., Gravel A., Gosselin J., Tremblay M. J., Flamand L. Activation of monocyte cyclooxygenase-2 gene expression by human herpesvirus 6: role for cyclic AMP-responsive element-binding protein and activator protein-1 // J. Biol. Chem. 2017. Vol. 27, Iss. 6. Р. 30665–30674. https://doi.org/10.1074/jbc.M203041200