Pairing of cholesterol with oxidized phospholipid species in lipid bilayers

Abstract

We claim that (1) cholesterol protects bilayers from disruption caused by lipid oxidation by sequestering conical shaped oxidized lipid species such as 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PZPC) away from phospholipid, because cholesterol and the oxidized lipid have complementary shapes and (2) mixtures of cholesterol and oxidized lipids can self-assemble into bilayers much like lysolipid–cholesterol mixtures. The evidence for bilayer protection comes from molecular dynamics (MD) simulations and dynamic light scattering (DLS) measurements. Unimodal size distributions of extruded vesicles (LUVETs) made up of a mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and PZPC containing high amounts of PZPC are only obtained when cholesterol is present in high concentrations. In simulations, bilayers containing high amounts of PZPC become porous, unless cholesterol is also present. The protective effect of cholesterol on oxidized lipids has been observed previously using electron paramagnetic resonance (EPR) and electron microscopy imaging of vesicles. The evidence for the pairing of cholesterol and PZPC comes mainly from correlated 2-D density and thickness plots from simulations, which show that these two molecules co-localize in bilayers. Further evidence that the two molecules can cohabitate comes from self-assembly simulations, where we show that cholesterol-oxidized lipid mixtures can form lamellar phases at specific concentrations, reminiscent of lysolipid–cholesterol mixtures. The additivity of the packing parameters of cholesterol and PZPC explains their cohabitation in a planar bilayer. Oxidized lipids are ubiquitously present in significant amounts in high- and low-density lipoprotein (HDL and LDL) particles, diseased tissues, and in model phospholipid mixtures containing polyunsaturated lipids. Therefore, our hypothesis has important consequences for cellular cholesterol trafficking; diseases related to oxidized lipids, and to biophysical studies of phase behaviour of cholesterol-containing phospholipid mixtures.

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

“…Indeed, the few reports of PGPC incorporation into multicomponent bilayers (composed of one PC and cholesterol) focus on the effects of cholesterol on lipid mobility and stability of the bilayer structure; POVPC is not considered. Cholesterol, which resides below phospholipid headgroups and provides a potential hydrogen-binding partner for oxPCs, tends to draw PGPC from its position, 1-2 Å farther from the center of the bilayer, toward a position more in line with other membrane phospholipids (77,78). Our simulations likewise indicate that PGPC headgroups reside~2 Å farther from the bilayer center than those of POPC and DPPC; there, the PGPC phosphate group coincides with that of SM, which, unlike cholesterol, tends to sit above the phosphate groups of other PCs.…”

Oxidized Lipids Decrease Phagocytic Activity of ARPE‐19 Cells In Vitro

“…It is known that the presence of oxidation products such as lysolipids and/or truncated phospholipids in the liposome membrane may affect the liposome shape, size, and curvature . It has been shown, that polydispersity of liposomes containing at least 50% of oxidized phospholipids is higher than those made of non‐oxidized lipids and becomes bimodal . However, the observed differences in the average diameter of prepared LUV and their moderate polydispersity index were not significant.…”

“…[32][33][34] It has been shown, that polydispersity of liposomes containing at least 50% of oxidized phospholipids is higher than those made of nonoxidized lipids and becomes bimodal. [35] However, the observed differences in the average diameter of prepared LUV and their moderate polydispersity index were not significant. Thus, the interaction of the prepared LUV with ARPE-19 cells should be comparable.…”

Polyunsaturated chains in asymmetric lipids disorder raft mixtures and preferentially associate with α-Synuclein

“…Lipids were constructed using previously published MARTINI parameters. Palmitic acid (P) and linoleic acid (Li) chains were modeled with four MARTINI beads [26,29], stearic acid (S) was modeled with five [30], and docosahexaenoic acid (D) was modeled with six (Table S1) [31]. Each system was run in an isothermal-isobaric ensemble (NPT) using the velocity-rescaling thermostat [32], and Berendsen barostat [33], with a temperature of 295 K and compressibility of 3e–4 bar-1 with a 10 fs time step.…”