Abstract 14758: Contrasting Effects of Phospholipid Linked Eicosapentaenoic Acid and Arachidonic Acid on Membrane Structure and Stability

Abstract

Background: Treatment with prescription, high dose, stable icosapent ethyl (IPE), which is metabolized to eicosapentaenoic acid (EPA), significantly reduced clinical events in high-risk patients with either cardiovascular disease or diabetes plus other risk factors (REDUCE-IT). Previous studies suggest that the benefits of EPA, an omega-3 fatty acid (O3FA), correlate positively with its levels and ratio to arachidonic acid (AA) in circulation and cellular membranes. Unlike EPA, AA is an omega-6 fatty acid (O6FA) that, along with its metabolites, contributes to inflammation and diabetes. Objective: The purpose of this study was to compare the separate and combined effects of phospholipid-linked EPA and AA on membrane structure. Methods: Small angle x-ray diffraction approaches compared the effects of 1-palmitoyl-2-eicosapentaenoyl-sn-glycero-3-phosphocholine (PL-EPA) and 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PL-AA) at a 1:20 ratio in membranes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and cholesterol (C) at a 0.3:1 C:PL ratio. As a control, we also evaluated membranes consisting of POPC and C only at the same C:PL ratio. Electron density profiles (electrons/Å 3 vs Å) generated from the diffraction data served to determine membrane structure, including its width or d -space, at 1 Å resolution. Results: Addition of PL-EPA increased membrane hydrocarbon core electron density over a broad area ± 0-10 Å from the membrane center, indicating a stabilizing effect on surrounding phospholipid acyl chains. By contrast, PL-AA caused a smaller, bimodal increase in electron density centered at ± 7 Å from the center of the membrane corresponding to its terminal double bonds. The membrane widths of the PL-EPA and PL-AA containing membranes were similar at 58 ± 0.7 Å and 57 ± 0.5 Å, respectively. The combination of PL-EPA with PL-AA highly attenuated the stabilizing effects of EPA on the membrane. Conclusion: PL-EPA causes membrane stability in a manner that is disrupted by the presence of PL-AA. The contrasting effects of PL-EPA and PL-AA on membrane structure may contribute to differences in biological activity.