Molecular Mechanisms of Palmitic Acid Augmentation in COVID-19 Pathologies

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 2.7 million lives globally. Obesity has been associated with increased severity and mortality of COVID-19. However, the molecular mechanisms by which obesity exacerbates COVID-19 pathologies are not well-defined. The levels of free fatty acids (FFAs) are elevated in obese subjects. This study was therefore designed to examine how excess levels of different FFAs may affect the progression of COVID-19. Biological molecules associated with palmitic acid (PA) and COVID-19 were retrieved from QIAGEN Knowledge Base, and Ingenuity Pathway Analysis tools were used to analyze these datasets and explore the potential pathways affected by different FFAs. Our study found that one of the top 10 canonical pathways affected by PA was the coronavirus pathogenesis pathway, mediated by key inflammatory mediators, including PTGS2; cytokines, including IL1β and IL6; chemokines, including CCL2 and CCL5; transcription factors, including NFκB; translation regulators, including EEF1A1; and apoptotic mediators, including BAX. In contrast, n-3 fatty acids may attenuate PA's activation of the coronavirus pathogenesis pathway by inhibiting the activity of such mediators as IL1β, CCL2, PTGS2, and BAX. Furthermore, PA may modulate the expression of ACE2, the main cell surface receptor for the SARS-CoV-2 spike protein.

Keywords: COVID-19; chemokines; cytokines; n-3 fatty acid; obesity; palmitic acid.

Figure 1

Canonical pathway analysis of PA-associated molecules. PA-associated molecules were retrieved from QKB and subjected to Core Analysis in IPA. Top 10 canonical pathways were presented with their respective p-values calculated using Benjamini–Hochberg corrected Fisher’s exact test.

Figure 2

35 biological molecules were found to be overlapped between PA- and COVID-19-associated molecules, including those involved in ER/oxidative stress, liver function, immune regulation, metabolism, and translation regulation.

Figure 3

The paths from PA to coronavirus pathogenesis pathway were established using the “Path Explorer” tool in IPA, and increased level of PA was simulated using the “MAP” tool in IPA.

Figure 4

The effects of n-3 fatty acids on the paths from PA to coronavirus pathogenesis pathway using the “Path Explorer” and “MAP” tools in IPA. (A) Increased level of PA and decreased level of n-3 FAs were simulated using the “MAP” tool in IPA. (B) Decreased level of PA and increased level of n-3 FAs were simulated using the “MAP” tool in IPA.

Figure 5

Molecular mediators on the paths from PA to COVID pathogenesis were mapped onto the coronavirus pathogenesis pathway. These mediators and the affected functions were highlighted in green.

Figure 6

The paths from PA to ACE2 mediated by molecules overlapped by PA- and COVID-19-associated molecules and involved in PA-induced activation of the coronavirus pathogenesis pathway. The paths were explored using the “Path Explorer” tool in IPA, and elevated level of PA was simulated using the “MAP” tool in IPA.