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PubMed2002

Structural, dynamic and mechanical properties of POPC at low cholesterol concentration studied in pressure/temperature space.

We have studied the structural, dynamic and mechanical properties of 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphatidylcholine (POPC)/cholesterol binary mixtures by small-angle X-ray scattering. Our investigations were concentrated on the biologically most relevant pressure-temperature-cholesterol regime, i.e. the liquid crystalline phase and its phase boundary to the lamellar gel phase within a cholesterol concentration up to 25 mol%. From the dependence of the transition pressure we derived a value of 19 kJ/mol for the transition enthalpy Delta H(m) of POPC in excess water. With increasing cholesterol concentration, Delta H(m) drops to about 7 kJ/mol at 20 mol% cholesterol. Time-resolved pressure-scan (p-scan) and temperature-jump (T-jump) experiments reveal that at low cholesterol content (<5-8 mol%) the fluidity and also the bilayer compressibility increase remarkably. In contrast, at concentrations between 5 and 25 mol% cholesterol the bilayer becomes again more rigid and the lipid bilayer spacing increases about 2 A. Theses changes are attributed to the onset of phase separation between liquid disordered and liquid ordered phases. The fluid-fluid miscibility gap for this mono-unsaturated lecithin species is strongly enlarged compared with saturated lecithins.

Cholesterol↗
PubMed1976

Dynamic surface tension properties of mixed lecithin-cholesterol films related to the respiratory mechanics.

A bubble method was used to record dynamic area/surface tension diagrams of mixed lecithin-cholesterol films prepared at different weight ratios. The lecithin/cholesterol weight ratios were: 1:2, 1:1, 4:1, 6:1, 8:1 and 12:1. The minimum surface tension is about 20 dyn/cm for all weight ratios at amplitudes of 75, 25, 12.5, 6 and 3% area oscillation. The maximum surface tension depends on both the amplitude of area oscillation and the lecithin/cholesterol weight ratio. The maximum surface tension increases with increasing amplitude. At the amplitudes 25, 12.5, 6 and 3% the maximum surface tension is significant higher at the weight ratios 1:2 and 1:1 compared to the other ratios. In addition, equilibrium surface tensions during interruptions of the oscillation at maximum and minimum area were recorded. The equilibrium surface tension increases with increasing amplitude up to 25% area oscillation. A static hysteresis seems to remain. Some consequences regarding the pulmonary respiratory mechanics are discussed.

Cholesterol↗
PubMed2004

Lessons of slicing membranes: interplay of packing, free area, and lateral diffusion in phospholipid/cholesterol bilayers.

We employ 100-ns molecular dynamics simulations to study the influence of cholesterol on structural and dynamic properties of dipalmitoylphosphatidylcholine bilayers in the fluid phase. The effects of the cholesterol content on the bilayer structure are considered by varying the cholesterol concentration between 0 and 50%. We concentrate on the free area in the membrane and investigate quantities that are likely to be affected by changes in the free area and free volume properties. It is found that cholesterol has a strong impact on the free area properties of the bilayer. The changes in the amount of free area are shown to be intimately related to alterations in molecular packing, ordering of phospholipid tails, and behavior of compressibility moduli. Also the behavior of the lateral diffusion of both dipalmitoylphosphatidylcholine and cholesterol molecules with an increasing amount of cholesterol can in part be understood in terms of free area. Summarizing, our results highlight the central role of free area in comprehending the structural and dynamic properties of membranes containing cholesterol.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Filipin and its interaction with cholesterol in aqueous media studied using static and dynamic light scattering.

Aggregation of filipin in aqueous medium and filipin-induced changes in cholesterol micelles have been studied using intensity and dynamic light scattering. The dependencies of filipin aggregate dimensions on concentration, solvent, and temperature were studied, and revealed that the aggregates do not have a well-defined geometry, i.e., a critical micelle concentration cannot be detected and stable structures are not formed. The aggregates are of size Rg approximately 110 nm and Rh approximately 63 nm, referring to the radius of gyration and hydrodynamic radius, respectively. In the concentration range studied (1 microM < C < 30 microM), a low molecular weight species (monomer/dimer) is always present together with the aggregates. In ethanol/water mixtures, large (Rg approximately 500 nm), narrow distribution aggregates are formed in the water volume fraction range 0.45 < phi H2O < 0.65. Aggregation also occurs on changing the temperature; In the range 7-37 degrees C, smaller aggregates (10-30 nm form and the process is only partially reversible. No pronounced effect of filipin on the structure of the cholesterol micelles was observed (a small increase in Rg and Rh is noted). These results rule out any "specificity" for the filipin interactions with cholesterol, which has been considered a key event in the filipin biochemical mode of action. A reevaluation of this question is suggested and some alternatives are advanced.

Biopolymers↗
PubMed1986

A quantitative dynamic concept of the interphase partition of lipids: application to bile salt-lecithin-cholesterol mixed micelles.

A system is proposed for a quantitative classification of lipids, based on interphase partition coefficients. This system enables calculation of exchanges of lipid molecules between phases. The mass/volume chemical unit mol X cm-3, strictly derived from the CGS system, is used, thus simplifying mathematical relations. Applied to bile salt-lecithin-cholesterol mixed micelles, this dynamic concept gives new insight into the variations of physico-chemical parameters. Experimental results obtained with the glycodesoxycholate and the taurocholate show a striking difference in partition coefficients between aqueous and mixed bile salt-lecithin interfacial phases. A new model applying triangular co-ordinates to a bile salt-lecithin-cholesterol mixed lipid phase is described.

Bile Acids and Salts↗
PubMed1975

An ESR Spin label study of structural and dynamical properties of oriented lecithin-cholesterol multibilayers.

Oriented dipalmitoyllecithin-cholesterol multibilayers with 11% water have been studied with the cholestane spin label. From the ESR spectra the order parameters and the mobility of the spin label about its long axis have been calculated. The results on pure lecithin multibilayers indicate a transition from gel to liquid crystalline phase at 52 plus or minus 2 degrees C. In the gel phase the lecithin alkyl chains are highly ordered, but tilted with respect to the normal to the bilayers by about 25 degrees. Above 52 degrees C the tilt disappears and the mobility of the cholestane spin label increases, indicating an increase of mobility of the lecithin alkyl chains. When cholesterol is added, below about 52 degrees C a decrease of order is found. Furthermore, already small cholesterol contents (smaller than or equal to 10 mole %) remove the tilt. Above about 52 degrees C cholesterol improves the order by decreasing the amplitude of the librational motions. Cholesterol lowers the transition temperature of the system and reduces the mobility of the lecithin alkyl chains in the liquid crystalline phase. However an increase in mobility is found at cholesterol contents up to 10 mole %. A very broad phase transition is observed at 50 mole % cholesterol. In all systems an increase in temperature results in a reduction of order through an increase of the amplitude of the librational motions of the molecules. The librational motions are to some extent cooperative. The asymmetry of the order matrix is found to be a measure for the lateral ordering. Cholesterol increases the lateral ordering, indicating that the flat cholesterol molecules orient parallel to each other.

Binding Sites↗
PubMed1980

Factors determining to biotransformation of cholesterol to bile acids in the rat: development of a new model.

This paper proposes a model for cholesterol metabolism in the rat based on extensive data obtained on rats in isotopic equilibrium with radioactive cholesterol. These data reveal that the rate of bile acid synthesis is closely related to cholesterol input. Hence the transformation of cholesterol into bile acids is conceived as a determinative process for the dynamics of the cholesterol system in the rat. This process is not per se regulated if the definition of regulation is as follows: to maintain constant a variable. In fact, the control of the transformation is dependent on the particulate transport of the plasma lipoproteins into the liver. In other words, from a physiological point of view, the process governing the net removal of cholesterol from the plasma into the liver is the limiting step for the cholesterol transformation into bile acids. Temporary losses or gains of cholesterol by the system modify the flow of the cholesterol transformation into bile acids during a transitory period. The effect of the exogenous taurocholate is so interpreted. Because this bile acid seems to act initially on the capacity of the liver to esterify free cholesterol, there results a loss of cholesterol which cannot be transformed into bile acids.

Animals↗
PubMed1998

Single-molecule enzymatic dynamics.

Enzymatic turnovers of single cholesterol oxidase molecules were observed in real time by monitoring the emission from the enzyme's fluorescent active site, flavin adenine dinucleotide (FAD). Statistical analyses of single-molecule trajectories revealed a significant and slow fluctuation in the rate of cholesterol oxidation by FAD. The static disorder and dynamic disorder of reaction rates, which are essentially indistinguishable in ensemble-averaged experiments, were determined separately by the real-time single-molecule approach. A molecular memory phenomenon, in which an enzymatic turnover was not independent of its previous turnovers because of a slow fluctuation of protein conformation, was evidenced by spontaneous spectral fluctuation of FAD.

Binding Sites↗
PubMed1987

Freeze-fracture analysis of cholesterol in muscle plasma membrane of Fukuyama-type congenital muscular dystrophy.

We used digitonin in freeze-fracture analysis of the muscle plasma membrane cholesterol content in six patients with Fukuyama-type congenital muscular dystrophy and six control children. A significantly greater proportion of surface area was taken up by digitonin-cholesterol complexes in the patients (51.2% +/- 4.7%) than in controls (31.9% +/- 2.9%) (P less than 0.01). Since membrane cholesterol has a dynamic regulatory function in affecting the activity of membrane-bound proteins, the increased cholesterol content in the patients suggests a functional abnormality of the muscle plasma membrane in this disease.

Cell Membrane↗
PubMed2004

Dynamic molecular structure of DPPC-DLPC-cholesterol ternary lipid system by spin-label electron spin resonance.

The hydrated ternary lamellar lipid mixture of dipalmitoyl-PC/dilauroyl-PC/cholesterol (DPPC/DLPC/Chol) has been studied by electron spin resonance (ESR) to reveal the dynamic structure on a molecular level of the different phases that exist and coexist over virtually the full range of composition. The spectra for more than 100 different compositions at room temperature were analyzed by nonlinear least-squares fitting to provide the rotational diffusion rates and order parameters of the end-chain labeled phospholipid 16-PC. The ESR spectra exhibit substantial variation as a function of composition, even though the respective phases generally differ rather modestly from each other. The Lalpha and Lbeta phases are clearly distinguished, with the former exhibiting substantially lower ordering and greater motional rates, whereas the well-defined Lo phase exhibits the greatest ordering and relatively fast motional rates. Typically, smaller variations occur within a given phase. The ESR spectral analysis also yields phase boundaries and coexistence regions which are found to be consistent with previous results from fluorescence methods, although new features are found. Phase coexistence regions were in some cases confirmed by observing the existence of isosbestic points in the absorption mode ESR spectra from the phases. The dynamic structural properties of the DPPC-rich Lbeta and DLPC-rich Lalpha phases, within their two-phase coexistence region do not change with composition along a tie-line, but the ratio of the two phases follows the lever rule in accordance with thermodynamic principles. The analysis shows that 16-PC spin-label partitions nearly equally between the Lalpha and Lbeta phases, making it a useful probe for studying such coexisting phases. Extensive study of two-phase coexistence regions requires the determination of tie-lines, which were approximated in this study. However, a method is suggested to accurately determine the tie-lines by ESR.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1980

A new view of human cholesterolemia.

As the inflows in the cholesterol system by absorption and synthesis are known, laws governing the cholesterolemia of rats in dynamic equilibria have recently been deduced. The method of analysis used for rats was applied in this theoretical work to data obtained by various authors with normal men. Because the sum of the inflows are only furnished, the method cannot be developed completely. Nevertheless it appears that the laws should be common to rats and humans. According to this hypothesis, the major deduction is that the dynamics of plasma cholesterol is assured by a process whose parameter is a linear function of the synthesis flow. Consequently the concentration of cholesterol of the synthesis source is as lower as the synthesis flow higher. The turnover of alimentary cholesterol in the plasma follows that of synthesized cholesterol. Hence an increase of the synthesis flow also causes a decrease in the concentration of cholesterol from the alimentary source. Simultaneously however this latter concentration is proportional to the absorption flow of alimentary cholesterol. Application of the analysis method to data obtained from patients with various disorders suggests that their cholesterol-system is intrinsically the same as that of normal men. But it could not be shown whether the values of two constants involved in the parameter equation are modified or not.

Absorption↗
PubMed1979

The role of the gallbladder in the pathogenesis of cholesterol gallstones.

During the past century, a variety of explanations have been proposed to explain the pathogenesis of cholesterol gallstones. Early attempts to account for the phenomenon of cholelithiasis focused on events in the gallbladder and stressed mucosal inflammatory changes, gallbladder stasis, stratification of bile, and absorption of bile salts from a damaged mucosa. The advent of the concept of "lithogenic bile" redirected attention to the liver and led to the proposal that an enzyme-mediated genetic and/or metabolic defect is the initiator of cholesterol cholelithiasis. While recognizing that the pathogenesis of gallstones is probably multifactorial, alterations in gallbladder and biliary ductal motor function constitute a plausible, but as yet unexplored, mechanism for alterations in enterohepatic circulation dynamics and subsequent cholesterol cholelithiasis. Gallbladder motor function is a complex phenomenon influenced by dynamic compliance, autonomic pharmacology, hormonal responses, and sphincter dynamics. Attempts to describe these aspects of biliary physiology may characterize the next phase in our understanding of the pathogenesis of cholesterol cholelithiasis.

Bile Acids and Salts↗
PubMed1991

Effect of cholesterol and lanosterol on the structure and dynamics of the cell membrane of Mycoplasma capricolum. Deuterium nuclear magnetic resonance study.

Deuterium nuclear magnetic resonance (NMR) techniques were employed to study the effect of sterols on the composition and dynamics of the membrane lipids of Mycoplasma capricolum, a natural fatty acid auxotroph that requires sterols for growth. The membrane lipids of cells grown in modified Edwards medium supplemented with cholesterol, oleic acid (OA), and palmitic acid (PA) were composed primarily of phosphatidylglycerol (PG) (60%) and cardiolipin (CL) (35%). The incorporation of cholesterol and the cellular OA/PA ratio increased nonlinearly with increases in exogenous cholesterol level, whereas the levels of phospholipid increased only slightly. At the growth temperature, 37 degrees C, the residual deuterium quadrupole splittings were found to be 43-46 kHz for cells grown with (7,7,8,8-2H4) PA and 1.25 micrograms/ml (30 mol%) to 10 micrograms/ml (50 mol%) cholesterol, respectively, similar to that found in the cholesterol/lecithin binary dispersions of similar cholesterol contents. Deuterium T2e of these samples were found to be 170 +/- 10 microseconds and were independent of cellular cholesterol content. In comparison, T2e of the corresponding lipid extracts were longer (320-420 microseconds) and dependent on cholesterol content. Thus, lipid-protein interactions in the cell membrane is the dominant mechanism responsible for the reduced T2e. At lower temperatures, spectra indicative of the coexistence of gel and liquid-crystalline states were observed for cells having low cholesterol levels. For both cell membrane and membrane lipid extract containing 50 mol% cholesterol, T2e was found to be constant at the temperature range from 15 to 40 degrees C. On the other hand, T2e of cell membrane containing 30 mol% cholesterol decreased linearly at 3.2 microseconds/degrees C. T2e of the corresponding lipid extract showed much stronger temperature variation. Cells containing 39 mol% lanosterol were found to have a quadrupole splitting of 39 kHz, broader than that of the cholesterol-free lecithin dispersion (less than 30 kHz) but less than that of cell membrane containing 30 mol% cholesterol (43 kHz). T2e of the lanosterol sample was found to be 130 +/- 10 microseconds which decreased linearly at a slope similar to that observed for the low cholesterol sample. Therefore, although lanosterol appeared to be capable of modulating cell membrane physical properties it is less effective than cholesterol. When growth rates were correlated with NMR parameters, we found that the membranes of faster growing cells were also more ordered. In contrast, the T2e of the cells of M. capricolum seemed to be maintained at a relatively constant value around 170 microseconds.

Biophysical Phenomena↗
PubMed1999

Effects of cannabinoids in membrane bilayers containing cholesterol.

The thermotropic and dynamic properties of the biologically active Delta(8)-tetrahydrocannabinol (Delta(8)-THC) and its inactive congener O-methyl-Delta(8)-tetrahydrocannabinol (Me-Delta(8)-THC) in DPPC/cholesterol (CHOL) bilayers have been studied using a combination of DSC and solid-state NMR spectroscopy. The obtained results showed differential effects of the two cannabinoids under study. These are summarized as follows: (a) the presence of the active compound fluidizes more significantly the DPPC/CHOL bilayers than the inactive analog as it is revealed by DSC and NMR spectroscopy results; (b) cholesterol seems to play a significant role in the way cannabinoids act in membrane bilayers; (c) the observed additional peaks in (13)C/MAS-NMR spectra which were cannabinoid specific offer an evidence of their different dynamic properties in membranes. In particular, the aromatic part of the inactive cannabinoid appears more mobile than that of the active one. This finding is in agreement with previously obtained X-ray data which locate the inactive cannabinoid in the hydrophobic core of the bilayer while the active one in the polar region; and (d) the observed downfield shift of C-1 carbon in the preparation containing the active cannabinoid is a strong evidence that Delta(8)-THC resides nearby the polar region where also cholesterol is well known to locate itself. Such downfield shift is absent when Me-Delta(8)-THC is resided in the membrane bilayer. These differential effects of the two cannabinoids propose that the phospholipid/cholesterol core of the membrane may play an important role in the mode of cannabinoid action by regulating their thermotropic and dynamic properties.

1,2-Dipalmitoylphosphatidylcholine↗