Abstract 335: Distinct Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid Linked Phospholipids on Membrane Structure

Abstract

In REDUCE-IT, prescription eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), significantly reduced ischemic events in patients with diabetes or cardiovascular disease. Treatments containing docosahexaenoic acid (DHA) have not shown similar benefits in other trials. EPA and DHA differentially influence lipid oxidation, signal transduction, fluidity, and cholesterol domain formation, potentially due to distinct membrane interactions. Small angle x-ray diffraction approaches compared the separate and combined effects of 1-palmitoyl-2-eicosapentaenoyl-sn-glycero-3-phosphocholine (PL-EPA) and 1-palmitoyl-2-docosahexaenoic-sn-glycero-3-phosphocholine (PL-DHA) at a 1:20 ratio in membranes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (PL-OA) and cholesterol (C) at a 0.3:1 C:PL ratio. As a control, we also evaluated membranes consisting of PL-OA and C only. 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 (Fig. 1A). Addition of PL-EPA increased membrane hydrocarbon core electron density over a broad area ± 0-10 Å from the membrane center, indicating an energetically favorable extended membrane orientation for EPA, stabilized by van der Waals interactions (Fig. 1B). By contrast, PL-DHA increased electron density in the phospholipid head group region concomitant with disordering in the hydrocarbon core ± 0-9 Å (Fig. 1C). Addition of the PL-O3FAs did not alter the overall membrane width (57 ± 1 Å). The combination of PL-EPA with PL-DHA highly attenuated their separate effects on the hydrocarbon core and headgroup (Fig. 1D). The contrasting EPA and DHA effects on membrane structure signify distinct molecular orientations that may contribute to observed differences in biological activity.