Determination of Membrane Cholesterol Partition Coefficient Using a Lipid Vesicle–Cyclodextrin Binary System: Effect of Phospholipid Acyl Chain Unsaturation and Headgroup Composition

Niu, Shui-Lin; Litman, Burton J.

doi:10.1016/s0006-3495(02)75340-x

Cited by 221 publications

(232 citation statements)

References 41 publications

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“…This result is reproduced in MD simulations on an 18:0-22:6PC/chol (3:1 mol) bilayer that corroborates the sterol favors solvation by saturated over polyunsaturated chains [52]. Partition coefficients for cholesterol are also smaller in unilamellar vesicles composed of PC with DHA than less unsaturated chains [53]. We have provided unequivocal substantiation of poor affinity for the sterol by the greatly reduced solubility that was measured in PUFAcontaining membranes by x-ray diffraction and solid-state 2 H NMR [54].…”

Section: Pufa's Aversion To Cholesterolsupporting

confidence: 67%

The location and behavior of α‐tocopherol in membranes

Atkinson

Harroun

Wassall

et al. 2010

Molecular Nutrition Food Res

173

128

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Vitamin E (a-tocopherol) has long been recognized as the major antioxidant in biological membranes, and yet many structurally related questions persist of how the vitamin functions. For example, the very low levels of a-tocopherol reported for whole cell extracts question how this molecule can successfully protect the comparatively enormous quantities of PUFAcontaining phospholipids found in membranes that are highly susceptible to oxidative attack. The contemporary realization that membranes laterally segregate into regions of distinct lipid composition (domains), we propose, provides the answer. We hypothesize a-tocopherol partitions into domains that are enriched in polyunsaturated phospholipids, amplifying the concentration of the vitamin in the place where it is most needed. These highly disordered domains depleted in cholesterol are analogous, but organizationally antithetical, to the wellstudied lipid rafts. We review here the ideas that led to our hypothesis. Experimental evidence in support of the formation of PUFA-rich domains in model membranes is presented, focusing upon docosahexaenoic acid that is the most unsaturated fatty acid commonly found. Physical methodologies are then described to elucidate the nature of the interaction of a-tocopherol with PUFA and to establish that the vitamin and PUFA-containing phospholipids co-localize in non-raft domains.

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Section: Pufa's Aversion To Cholesterolsupporting

confidence: 67%

The location and behavior of α‐tocopherol in membranes

Atkinson

Harroun

Wassall

et al. 2010

Molecular Nutrition Food Res

173

128

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“…We speculate that s o phase formation is related to the high PE content of viral envelopes ( Supplementary Fig. 5 and Supplementary Table 2 online) as PE has low affinity for cholesterol 24,43,44 and high gel-fluid phase transition temperatures.…”

Section: Discussionmentioning

confidence: 99%

Progressive ordering with decreasing temperature of the phospholipids of influenza virus

Polozov¹,

Bezrukov²,

Gawrisch³

et al. 2008

Nat Chem Biol

211

159

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Using linewidth and spinning sideband intensities of lipid hydrocarbon chain resonances in proton magic angle spinning NMR spectra, we detected the temperature-dependent phase state of naturally occurring lipids of intact influenza virus without exogenous probes. Increasingly, below 41 1C ordered and disordered lipid domains coexisted for the viral envelope and extracts thereof. At 22 1C much lipid was in a gel phase, the fraction of which reversibly increased with cholesterol depletion. Diffusion measurements and fluorescence microscopy independently confirmed the existence of gel-phase domains. Thus the existence of ordered regions of lipids in biological membranes is now demonstrated. Above the physiological temperatures of influenza infection, the physical properties of viral envelope lipids, regardless of protein content, were indistinguishable from those of the disordered fraction. Viral fusion appears to be uncorrelated to ordered lipid content. Lipid ordering may contribute to viral stability at lower temperatures, which has recently been found to be critical for airborne transmission.Membranes of most enveloped viruses form by budding out from the plasma membranes of their host cells a highly select subset of plasma membrane components. In general, the selected membrane proteins are coded by the viral genome, whereas lipids are recruited from host membranes; however, the lipid composition of the viral envelope differs from that of the host membrane 1,2 and from other budding viruses 3 . The envelope of influenza contains higher amounts of both cholesterol 1 and glycosphingolipids 4 -lipids known to partition into the liquid ordered (l o ) phase. The l o phase is characterized by extended hydrocarbon chains having a reduced gauche-trans isomerization compared with those of the liquid disordered (l d ) phase, but having a similar rotational and translational mobility 5 . Liquid ordered phases are thought to be at the core of lipid rafts 6 , which are defined as transient membrane microdomains that are enriched in sphingolipids and cholesterol (1) 7 -a hypothesis that has generated much debate 8,9 .The influenza virus has played a pivotal role in the development of the raft hypothesis, starting with early studies that inferred ordered domains using spin probes 10-12 and fluorescence 13,14 and that suggested that an ordered lipid domain is selected in toto as the envelope during budding from the plasma membrane 15 . These lipids are either selected at the time of budding or pre-selected as the 'pre-envelope' suggested by clusters of the viral envelope protein hemagglutinin seen in immunoelectron microscopy 16 .Although detection of virus-sized domains of lipids (B100-nm diameter) is below the limit of resolution of fluorescent microscopy, large micrometer-sized membrane domains are reliably detected [17][18][19] . Recently, proton magic angle spinning NMR ( 1 H MAS NMR) has been used to determine the phase diagram of the same lipid compositions used to study large membrane domains in lipid bilayers and othe...

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“…Sterols are not ideal solutes dissolved in the hydrophobic core of the bilayer. Rather, they associate with the more polar lipids with varied strengths of interaction [11]. What matters most in these associations is the length of the non-polar chains of the polar lipids, the (un)saturation of their chains (i.e., the number, position and orientation [cis versus trans] of their double bonds), and the size and structure of their polar head groups [10]).…”

Section: Interactions Of Sterols With Phospholipidsmentioning

confidence: 99%

“…Perhaps a jump in plasma membrane cholesterol will, by passive partitioning, drive an increase in the intracellular membrane cholesterol level until the chemical potential equalizes among these compartments [59]. The low levels of cholesterol normally found in intracellular membranes such as ER and mitochondria would then reflect the known weak affinity for sterols of their phospholipids compared to those abundant in the plasma membrane, especially in its exofacial leaflet [10,11,62]. An alternative hypothesis is that sterols are pumped against their diffusional gradients so as to metabolically tune their concentration in each organelle.…”

Section: Cholesterol Activity and Cellular Cholesterol Homeostasismentioning

confidence: 99%

“…An alternative hypothesis is that sterols are pumped against their diffusional gradients so as to metabolically tune their concentration in each organelle. One line of reasoning that suggests an active process is that the partition coefficients for cholesterol among defined phospholipids span no more than a ~10-fold range [11]. But, if >50% of the cholesterol in fibroblasts is in the plasma membrane and ~0.5% in the ER, and these membrane compartments have a comparable abundance of phospholipid, their overall phospholipid partition coefficients would have to differ by about two orders of magnitude for passive equilibration to be the determinant of cholesterol distribution.…”

Section: Cholesterol Activity and Cellular Cholesterol Homeostasismentioning

confidence: 99%

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Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol

Lange

Steck

2008

Progress in Lipid Research

145

192

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We review evidence that sterols can form stoichiometric complexes with certain bilayer phospholipids, and sphingomyelin in particular. These complexes appear to be the basis for the formation of condensed and ordered liquid phases, (micro)domains and/or rafts in both artificial and biological membranes. The sterol content of a membrane can exceed the complexing capacity of its phospholipids. The excess, uncomplexed membrane sterol molecules have a relatively high escape tendency, also referred to as fugacity or chemical activity (and, here, simply activity). Cholesterol is also activated when certain membrane intercalating amphipaths displace it from the phospholipid complexes. Active cholesterol projects from the bilayer and is therefore highly susceptible to attack by cholesterol oxidase. Similarly, active cholesterol rapidly exits the plasma membrane to extracellular acceptors such as cyclodextrin and high-density lipoproteins. For the same reason, the pool of cholesterol in the ER (endoplasmic reticulum) increases sharply when cell surface cholesterol is incremented above the physiological set-point; i.e., equivalence with the complexing phospholipids. As a result, the escape tendency of the excess cholesterol not only returns the plasma membrane bilayer to its set point but also serves as a feedback signal to intracellular homeostatic elements to down-regulate cholesterol accretion.

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Determination of Membrane Cholesterol Partition Coefficient Using a Lipid Vesicle–Cyclodextrin Binary System: Effect of Phospholipid Acyl Chain Unsaturation and Headgroup Composition

Cited by 221 publications

References 41 publications

The location and behavior of α‐tocopherol in membranes

The location and behavior of α‐tocopherol in membranes

Progressive ordering with decreasing temperature of the phospholipids of influenza virus

Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol

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