Lipidomics-Based Cartography of Membrane Phospholipids Remodeling Uncovers Enzymatic Underpinnings of Cellular Dysfunction in Metabolic Syndrome Patients

Background: Metabolic syndrome (MetS) is linked with insulin resistance and low-grade chronic inflammation. Emerging evidence indicates that these features are associated with the disturbed membrane phospholipid composition but the enzymatic drivers of membrane remodeling in real-life MetS are still too poorly mapped. Objective: The overall design is to map membrane phospholipid remodeling through lipidomics and identify the enzymatic causes of cellular dysfunction of patients who have MetS. Methods: This is a hospital-based case-control study, 100 adults were witnessed (MetS, n=50; controls, n=50). Fasting clinical and biochemical parameters were measured, which included lipid profile, hs-CRP, fasting insulin and HOMA-IR. Plasma and PBMC lipid extracts were analysed by UHPLC -MS/MS lipidomics. Remodeling indices (LPC/PC, LPE/PE, saturation index, PUFA-enrichment) derived. PBMC enzymatic activities important to Lands' cycle (PLA2, LPCAT, ACSL4 and MBOAT7) were measured. Group comparisons, correction for multiple testing (fdr) correction for lipidomics, correlation and regression analysis were performed in multivariable. Results: MetS cases had greater insulin resistance and inflammation (HOMA-IR and hs-CRP; p<0.001). Lipidomics revealed an increase in the level of lysophospholipids (total LPC and LPE; p < 0.001; the level was statistically significant after a False Discovery 0.001) with a decrease in the level of structural phospholipids (PC and PE; p < 0.025; the level was statistically significant at False Discovery <= 0.025). Remodeling indices showed high LPC/PC and LPE/PE ratios and high saturation indices with depletion of the phospholipid species with the higher UFA content (p<0.001). Through enzymatic profiling, higher PLA2 and lower LPCAT, ACSL4 and MBOAT7 activities (p<=0.002) were found to be increased. PLA2 activity showed a positive correlation with LPC/PC (rho equal to 0.72 and HOMA-IR (rho equal to 0.59) and ACSL4 activity was positively correlated with arachidonoyl enrichment (rho equal to 0.66) (all p less than 0.001). LPC/PC ratio and PLA2 activity were independent predictors of HOMA-IR and ACSL4 activity was an inverse predictor of hs-CRP in the regression analysis. Conclusions: MetS is represented by a lipidomics signature of membrane phospholipid remodeling resulting from a lipid remodeling deacylation/reacylation imbalance - PLA2 activation _impaired reacylation capacity (LPCAT/ACSL4/MBOAT7). These enzymatically anchored remodeling indices have a strong link to insulin resistance and inflammation, providing support for their therapists or mechanistic biomarker value.'