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.
Highlights
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
Using TR-small angle neutron scattering (SANS), a noninvasive in situ technique that is able to track the movement of unaltered lipids and sterols, we obtained the flip-flop and exchange rates and energetics of cholesterol in PC membranes consisting of mixtures of saturated palmitoyl (16:0) and unsaturated oleolyl (18:1) tails
Starting from a fully saturated membrane (DPPC), we found that as the number of unsaturated lipid tails increases in the membrane, both flip-flop and exchange rates of cholesterol increase
Summary
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. 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.—Breidigan, J. The idea that cholesterol-lipid interactions, which vary according to lipid type, affect cholesterol’s affinity for certain membrane environments has incited numerous studies using model lipid systems. These studies have found that cholesterol interacts preferentially with saturated lipids [6, 7]. Even though cholesterol is thought of as highly mobile, flipping quickly between the membrane’s bilayered leaflets [13, 14], this higher affinity for saturated lipids or an environment enriched in saturated lipids could, slow down cholesterol flipping and, help keep cholesterol asymmetrically distributed across the PM, as recently reported by Liu et al [11]
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