Influence of the membrane environment on cholesterol transfer

Abstract

Cholesterol, an essential component in biological membranes, is highly unevenly distributed within the cell, with most localized in the plasma membrane while only a small fraction is found in the endoplasmic reticulum, where it is synthesized. Cellular membranes differ in lipid composition and protein content, and these differences can exist across their leaflets too. This thermodynamic landscape that cellular membranes impose on cholesterol is expected to modulate its transport. To uncover the role the membrane environment has on cholesterol inter- and intra-membrane movement, we used time-resolved small angle neutron scattering to study the passive movement of cholesterol between and within membranes with varying degrees of saturation content. We found that cholesterol moves systematically slower as the degree of saturation in the membranes increases, from a palmitoyl oleyl phosphotidylcholine membrane, which is unsaturated, to a dipalmitoylphosphatidylcholine (DPPC) membrane, which is fully saturated. Additionally, we found that the energetic barrier to move cholesterol in these phosphatidylcholine membranes is independent of their relative lipid composition and remains constant for both flip-flop and exchange at ∼100 kJ/mol. Further, by replacing DPPC with the saturated lipid palmitoylsphingomyelin, an abundant saturated lipid of the outer leaflet of the plasma membrane, we found the rates decreased by a factor of two. This finding is in stark contrast with recent molecular dynamic simulations that predict a dramatic slow-down of seven orders of magnitude for cholesterol flipping in membranes with a similar phosphocholine and SM lipid composition.

Comprehensive multiomics analysis of the effect of ginsenoside Rb1 on hyperlipidemia

“…Focusing on its lipid-lowering effects, PC helps cholesterol to dissolve more easily, which would suppress the buildup of cholesterol within arteries, thereby reducing the risk of atherosclerosis. In fact, PC helps lower in tissues throughout the body [ 29 ], making PC metabolism a crucial factor for decreasing bodily lipid levels.…”

Transverse distribution of plasma membrane bilayer cholesterol: Picking sides

“…As mentioned above, very slowly and/or incompletely reacting pools of membrane [ 3 H]cholesterol have been observed using cholesterol oxidase as a probe, and such kinetics were similarly ascribed to slow transbilayer diffusion . Slow flip rates have also been inferred from time‐resolved small angle neutron scattering studies . It is likely that, in some studies, there is actually rapid flip but only a fraction of the total cholesterol is detectable; this would lead to an overestimation of the inner leaflet pool; see .…”

“…50,97 Slow flip rates have also been inferred from time-resolved small angle neutron scattering studies. 112,113 It is likely that, in some studies, there is actually rapid flip but only a fraction of the total cholesterol is detectable; this would lead to an overestimation of the inner leaflet pool; see. 114 In particular, preparations of synthetic vesicle sometimes contain multivesicular contaminants; this would lead to the slow and limited accessibility of a fraction of their cholesterol at the exposed surface.…”

Neutron scattering in the biological sciences: progress and prospects

“…Such membrane asymmetry is of high physiological relevance, directing transmembrane signaling events, including transmembrane transport processes that establish ion gradients. Recent SANS studies have been able to quantify the energetic cost of maintaining lipid-composition asymmetry in membranes (Wah et al, 2017;Nakano et al, 2007;Garg et al, 2011;Breidigan et al, 2017).…”