EPA and DHA Interact Differentially with Cholesterol: Solid State 2H NMR of PUFA-Containing Phospholipids in Mixtures with Lipid raft Molecules

Abstract

A plethora of health benefits accompany dietary consumption of ω-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic (EPA, 20:5) and docosahexaenoic (DHA, 22:6) acids found in fish oils. An emerging view for one mechanism of action is that ω-3 PUFA incorporate into phospholipids of the plasma membrane and, due to their aversion for cholesterol, affect lateral organization. What is unclear is which component of fish oil drives the structural and concomitant functional changes. Here we test EPA vs. DHA in mixtures with the lipid raft molecules egg sphingomyelin (SM) and cholesterol. Our approach is to employ solid state 2H NMR to characterize the molecular organization of EPA-containing 1-[2H31]palmitoyl-2- eicosapentaenoylphosphatidylcholine ([2H31]16:0-20:5PC) and DHA-containing 1-[2H31]palmitoyl-2-docosahexaenoylphosphatidylcholine ([2H31]16:0-22:6PC), and of oleic acid (OA, 18:1)-containing 1-[2H31]palmitoyl-2-oleoylphosphatidylcholine ([2H31]16:0-18:1PC) as a control. Spectra for mixtures with SM and cholesterol (1:1:1 mol) support our model according to which poor affinity of PUFA for the sterol promotes the formation of highly disordered PUFA-rich/cholesterol-poor (non-raft) domains on the nanoscale. The novelty of the results lies in the enhanced effect seen for EPA relative to DHA. Less interaction with cholesterol is indicated by the smaller increase in sterol-induced order measured for [2H31]16:0-20:5PC compared to ([2H31]16:0-22:6PC, and a larger domain size is implied with EPA than DHA. We speculate that these preliminary observations at the molecular level may reflect a more influential role for EPA.