Increased consumption of long-chain marine n-3 polyunsaturated fatty acids (PUFA) has potential health benefits for the general population and for select clinical populations. However, several key limitations remain in making adequate dietary recommendations on n-3 PUFAs in addition to translating the fatty acids into clinical trials for select diseases. One major constraint is an incomplete understanding of the underlying mechanisms of action of n-3 PUFAs. In this review, we highlight studies to show n-3 PUFA acyl chains reorganize the molecular architecture of plasma membrane sphingolipid-cholesterol-enriched lipid rafts and potentially sphingolipid-rich cholesterol-free domains and cardiolipin-protein scaffolds in the inner mitochondrial membrane. We also discuss the possibility that the effects of n-3 PUFAs on membrane organization could be regulated by the presence of vitamin E (α-tocopherol), which is necessary to protect highly unsaturated acyl chains from oxidation. Finally, we propose the integrated hypothesis, based predominately on studies in lymphocytes, cancer cells, and model membranes, that the mechanism by which n-3 PUFAs disrupt signaling microclusters is highly dependent on the type of lipid species that incorporate n-3 PUFA acyl chains. The current evidence suggests that n-3 PUFA acyl chains disrupt lipid raft formation by incorporating primarily into phosphatidylethanolamines but can also incorporate into other lipid species of the lipidome.
Keywords: Lipid microdomains; Lipid rafts; Membrane structure; N-3 polyunsaturated fatty acids; Protein lateral organization; Vitamin E.
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