Magnification of Cholesterol-Induced Membrane Resistance on the Tissue Level: Implications for Hypoxia

Shea, Ryan; Smith, Casey R.; Pias, Sally C.

doi:10.1007/978-3-319-38810-6_6

Cited by 5 publications

(6 citation statements)

References 25 publications

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“…Subsequent investigations described this effect in detail, − showing that the effect of cholesterol in lipid membrane structures is exceptionally prominent at the level of the cholesterol ring. , Unbiased molecular dynamics (MD) simulations showed that the rate of spontaneous water translocation through a membrane decreases by a factor of 7 when the content of cholesterol is increased from 0 to 33 mol % . This is in agreement with experimental studies that reported a 4-fold reduction of water permeability through a bilayer containing 25 mol % of cholesterol compared to a pure phospholipid bilayer. ,− Cholesterol has also been shown to decrease the membrane permeability to ions, small neutral molecules like glucose, , and gases such as oxygen. , Recent MD simulation studies have further shown that the free energy barrier of translocating certain drugs and nanoparticles across a lipid bilayer increases with increasing cholesterol content. − In biological membranes, reduction of cholesterol concentration was observed to render them more permeable. , …”

Section: Introductionsupporting

confidence: 58%

“… 1 , 8 − 10 Cholesterol has also been shown to decrease the membrane permeability to ions, 11 small neutral molecules like glucose, 12 , 13 and gases such as oxygen. 14 , 15 Recent MD simulation studies have further shown that the free energy barrier of translocating certain drugs and nanoparticles across a lipid bilayer increases with increasing cholesterol content. 16 − 18 In biological membranes, reduction of cholesterol concentration was observed to render them more permeable.…”

Section: Introductionmentioning

confidence: 99%

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Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

et al. 2020

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Cholesterol renders mammalian cell membranes more compact by reducing the amount of voids in the membrane structure. Because of this, cholesterol is known to regulate the ability of cell membranes to prevent the permeation of water and water-soluble molecules through the membranes. Meanwhile, it is also known that even seemingly tiny modifications in the chemical structure of cholesterol can lead to notable changes in membrane properties. The question is, how significantly do these small changes in cholesterol structure affect the permeability barrier function of cell membranes? In this work, we applied fluorescence methods as well as atomistic molecular dynamics simulations to characterize changes in lipid membrane permeability induced by cholesterol oxidation. The studied 7β-hydroxycholesterol (7β-OH-chol) and 27-hydroxycholesterol (27-OH-chol) represent two distinct groups of oxysterols, namely, ring- and tail-oxidized cholesterols, respectively. Our previous research showed that the oxidation of the cholesterol tail has only a marginal effect on the structure of a lipid bilayer; however, oxidation was found to disturb membrane dynamics by introducing a mechanism that allows sterol molecules to move rapidly back and forth across the membrane—bobbing. Herein, we show that bobbing of 27-OH-chol accelerates fluorescence quenching of NBD-lipid probes in the inner leaflet of liposomes by dithionite added to the liposomal suspension. Systematic experiments using fluorescence quenching spectroscopy and microscopy led to the conclusion that the presence of 27-OH-chol increases membrane permeability to the dithionite anion. Atomistic molecular dynamics simulations demonstrated that 27-OH-chol also facilitates water transport across the membrane. The results support the view that oxysterol bobbing gives rise to successive perturbations to the hydrophobic core of the membrane, and these perturbations promote the permeation of water and small water-soluble molecules through a lipid bilayer. The observed impairment of permeability can have important consequences for eukaryotic organisms. The effects described for 27-OH-chol were not observed for 7β-OH-chol which represents ring-oxidized sterols.

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Section: Introductionsupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

et al. 2020

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“…Force-field parameters for O 2 were developed in our laboratory. As described in Shea et al (45), the bond length was set to 1.21 Å , with a vibrational force constant of 849.16 kcal/mol$Å 2 and all other parameters defined the same as the Lipid 11 carbonyl oxygen (oC) atom type, which originated with the General Amber Force Field (GAFF) (46). O 2 molecules were introduced into the simulation systems by replacing water molecules to reach a concentration of 200 mM O 2 for the entire water-lipid system.…”

Section: Simulationsmentioning

confidence: 99%

Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations

Dotson

Smith

Bueche

et al. 2017

Biophysical Journal

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Cholesterol is widely known to alter the physical properties and permeability of membranes. Several prior works have implicated cell membrane cholesterol as a barrier to tissue oxygenation, yet a good deal remains to be explained with regard to the mechanism and magnitude of the effect. We use molecular dynamics simulations to provide atomic-resolution insight into the influence of cholesterol on oxygen diffusion across and within the membrane. Our simulations show strong overall agreement with published experimental data, reproducing the shapes of experimental oximetry curves with high accuracy. We calculate the upper-limit transmembrane oxygen permeability of a 1-palmitoyl,2-oleoylphosphatidylcholine phospholipid bilayer to be 52 ± 2 cm/s, close to the permeability of a water layer of the same thickness. With addition of cholesterol, the permeability decreases somewhat, reaching 40 ± 2 cm/s at the near-saturating level of 62.5 mol % cholesterol and 10 ± 2 cm/s in a 100% cholesterol mimic of the experimentally observed noncrystalline cholesterol bilayer domain. These reductions in permeability can only be biologically consequential in contexts where the diffusional path of oxygen is not water dominated. In our simulations, cholesterol reduces the overall solubility of oxygen within the membrane but enhances the oxygen transport parameter (solubility-diffusion product) near the membrane center. Given relatively low barriers to passing from membrane to membrane, our findings support hydrophobic channeling within membranes as a means of cellular and tissue-level oxygen transport. In such a membrane-dominated diffusional scheme, the influence of cholesterol on oxygen permeability is large enough to warrant further attention.

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“…This increased resistance should correspond with a permeability reduction of similar magnitude. While modest on a single-membrane level, the rate-reducing effect should be amplified as oxygen is required to cross or circumvent multiple membranes on its path toward mitochondria buried within tissues [18]. …”

Section: Discussionmentioning

confidence: 99%

Predicted Decrease in Membrane Oxygen Permeability with Addition of Cholesterol

Angles

Dotson

Bueche

et al. 2017

Advances in Experimental Medicine and Biology

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Aberrations in cholesterol homeostasis are associated with several diseases that can be linked to changes in cellular oxygen usage. Prior biological and physical studies have suggested that membrane cholesterol content can modulate oxygen delivery, but questions of magnitude and biological significance remain open for further investigation. Here, we use molecular dynamics simulations in a first step toward reexamining the rate impact of cholesterol on the permeation of oxygen through phospholipid bilayers. The simulation models are closely compared with published electron paramagnetic resonance (EPR) oximetry measurements. The simulations predict an oxygen permeability reduction due to cholesterol but also suggest that the EPR experiments may have underestimated resistance to oxygen permeation in the phospholipid headgroup region.

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Magnification of Cholesterol-Induced Membrane Resistance on the Tissue Level: Implications for Hypoxia

Cited by 5 publications

References 25 publications

Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

Tail-Oxidized Cholesterol Enhances Membrane Permeability for Small Solutes

Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations

Predicted Decrease in Membrane Oxygen Permeability with Addition of Cholesterol

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