OxPAPC stabilizes liquid-ordered domains in biomimetic membranes.

Long-chain polyunsaturated fatty acids (PUFAs) are prone to nonenzymatic oxidation in response to differing environmental stressors and endogenous cellular sources. There is increasing evidence that phospholipids containing oxidized PUFA acyl chains control the inflammatory response. However, the underlying mechanism(s) of action by which oxidized PUFAs exert their functional effects remain unclear. Herein, we tested the hypothesis that replacement of 1-palmitoyl-2-arachidonyl-phosphatidylcholine (PAPC) with oxidized 1-palmitoyl-2-arachidonyl-phosphatidylcholine (oxPAPC) regulates membrane architecture. Specifically, with solid-state H NMR of biomimetic membranes, we investigated how substituting oxPAPC for PAPC modulates the molecular organization of liquid-ordered (L) domains. H NMR spectra for bilayer mixtures of 1,2-dipalmitoylphosphatidylcholine-d (an analog of DPPC deuterated throughout sn-1 and -2 chains) and cholesterol to which PAPC or oxPAPC was added revealed that replacing PAPC with oxPAPC disrupted molecular organization, indicating that oxPAPC does not mix favorably in a tightly packed L phase. Furthermore, unlike PAPC, adding oxPAPC stabilized 1,2-dipalmitoylphosphatidylcholine-d-rich/cholesterol-rich L domains formed in mixtures with 1,2-dioleoylphosphatidylcholine while decreasing the molecular order within 1,2-dioleoylphosphatidylcholine-rich liquid-disordered regions of the membrane. Collectively, these results suggest a mechanism in which oxPAPC stabilizes L domains-by disordering the surrounding liquid-disordered region. Changes in the structure, and thereby functionality, of L domains may underly regulation of plasma membrane-based inflammatory signaling by oxPAPC.