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Results for “Cholesterol dynamics”

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PubMed1988

Globoside with spin-labelled fatty acid: bilayer lateral distribution and immune recognition.

We have critically addressed the question of lateral distribution of glycolipids in bilayer membranes, and the effect of glycolipid fatty acid chain length upon such distribution. For this purpose we synthesised the complex neutral glycosphingolipid, globoside, with spin-labelled fatty acid. Base hydrolysis to remove the natural fatty acid was found to deacetylate the GalNAc residue concomitantly, necessitating application of the synthetic route described for gangliosides by Neuenhofer et al. (Biochemistry 24, 525-532 (1985)). Globosides were produced with 18-carbon and 24-carbon fatty acids bearing a spin label at the C-16 position. Spin-labelled globosides were incorporated at 2 and 10 mol% into rigid, highly cooperative bilayer matrices of 1,2-dipalmitoylglycerophosphocholine (DPPC) and also into semi-fluid, non-cooperative membranes of DPPC/cholesterol. Recorded electron paramagnetic resonance (EPR) spectra were analysed by comparison with a library of standards representing samples of known composition. Spectra were manipulated using a computer program which permitted linear combination of standards to stimulate coexistence of laterally separated domains of different composition. The most important conclusions were as follows: (1) at least 80% of the globoside was definitely not confined to domains highly enriched in glycolipid, although there was evidence of binary-phase separation in the rigid DPPC/globoside matrix; (2) the presence of 33 mol% cholesterol reduced the evidence of globoside phase separation; (3) there was remarkably little difference in results whether the globoside fatty acid chain length was similar to that of the phospholipid host matrix or eight carbons longer. Temperature profiles derived over the phase-transition region of DPPC using spin-labelled globoside or an unattached amphiphilic spin label were consistent with these findings. The same systems lent themselves to consideration of the role of glycolipid fatty acid chan length and cholesterol in determining glycolipid crypticity in membranes: (1) polyclonal anti-globoside IgG bound to globoside in DPPC liposomes without inducing agglutination. (2) The same antibodies did agglutinate DPPC/cholesterol liposomes bearing globoside. (3) The effect of cholesterol probably was upon glycolipid dynamics or attitude in the membrane, rather than upon distribution. (4) These observations were basically unaffected by the choice of 18-carbon vs. 24-carbon glycolipid fatty acids.(ABSTRACT TRUNCATED AT 400 WORDS)

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2004

Impact of cholesterol on voids in phospholipid membranes.

Free volume pockets or voids are important to many biological processes in cell membranes. Free volume fluctuations are a prerequisite for diffusion of lipids and other macromolecules in lipid bilayers. Permeation of small solutes across a membrane, as well as diffusion of solutes in the membrane interior are further examples of phenomena where voids and their properties play a central role. Cholesterol has been suggested to change the structure and function of membranes by altering their free volume properties. We study the effect of cholesterol on the properties of voids in dipalmitoylphosphatidylcholine (DPPC) bilayers by means of atomistic molecular dynamics simulations. We find that an increasing cholesterol concentration reduces the total amount of free volume in a bilayer. The effect of cholesterol on individual voids is most prominent in the region where the steroid ring structures of cholesterol molecules are located. Here a growing cholesterol content reduces the number of voids, completely removing voids of the size of a cholesterol molecule. The voids also become more elongated. The broad orientational distribution of voids observed in pure DPPC is, with a 30% molar concentration of cholesterol, replaced by a distribution where orientation along the bilayer normal is favored. Our results suggest that instead of being uniformly distributed to the whole bilayer, these effects are localized to the close vicinity of cholesterol molecules.

Algorithms↗

PubMed1981

Theory for nuclear magnetic relaxation of probes in anisotropic systems: application of cholesterol in phospholipid vesicles.

The nuclear magnetic relaxation of a nucleus in a cylindrical probe embedded in a bilayer vesicle is considered. The probe is assumed to diffuse freely about its unique (C infinity) symmetry axis with an effective correlation time tau parallel, and the C infinity axis moves in a potential which is azimuthally symmetric about a director, with an effective correlation time tau perpendicular. The overall isotropic rotational correlation time of the membrane is tau M. Dipolar relaxation and, in the special case that the relevant tensors are axially symmetric, quadrupolar and chemical shift anisotropy relaxation are treated. An expression for the appropriate correlation function is derived which depends on the above effective correlation times, on the order parameter of the C infinity axis of the probe, and on the angle (beta) which in the case of dipolar relaxation of a protonated 13 C nucleus is between the 13 C-H vector and the C infinity axis of the probe. A significant feature of this formulation of the dynamics is that no assumptions need be made concerning the relative order of magnitudes of the effective correlation times and the Larmor frequencies (e.g., such as the extreme narrowing limit). The model not only can be used to describe the dynamics of probes such as cholesterol in membranes but also is applicable to certain anisotropic internal motions in proteins. In addition, by allowing the angle beta to fluctuate, a simple model for segmental motion in lipid molecules can be obtained. As an application, 13 C nuclear magnetic relaxation experiments on cholesterol in sonicated egg yolk phosphatidylcholine vesicles are interpreted within the framework of the model. The remarkable observation that the protonated C6 carbon has a line width which is much narrower than those of other methine carbons and is in fact comparable to the line width of the nonprotonated C5 carbon is shown to be the consequence of (1) the anisotropic nature of the cholesterol motion in the bilayer and (2) the fact that angle between the 13 C6-H vector and the long axis of cholesterol is very close to the "magic" value of 54.7 degrees.

Animals↗

PubMed1991

[Dynamics of the lipoprotein distribution in early hypercholesterolemia characterizes the activation of cholesterol transport].

Using gradient gel electrophoresis, the levels of major classes of rabbit blood sera lipoproteins were studied over a period of 28 days. Hypercholesterolemia persisted up to the 4th day with a subsequent decrease. This was paralleled with an increase in the levels of triglyceride-rich and apoB-containing particles. The decrease of the electrophoretic mobility of low density lipoproteins correlated with an increased content of the intermediate fraction. On the 28th day after the beginning of experiment the concentration of total high density lipoproteins showed an increase. The subfractional redistribution of HDL3 and HDL2 subclasses pointed to the stimulation of the accepting process and the overall reverse cholesterol transport system. A comparison of experimental results with literary data allowed to conclude that the relative decrease of the serum cholesterol level typical of hypercholesterolemia of one month duration is due to the activation of specific and nonspecific preventive mechanisms.

Animals↗

PubMed2006

Effect of cholesterol on lateral diffusion of fluorescent lipid probes in native hippocampal membranes.

Cholesterol is an abundant lipid of mammalian membranes and plays a crucial role in membrane organization, dynamics, function and sorting. The role of cholesterol in membrane organization has been a subject of intense investigation that has largely been carried out in model membrane systems. An extension of these studies in natural membranes, more importantly in neuronal membranes, is important to establish a relationship between disease states and changes in membrane physical properties resulting from an alteration in lipid composition. We have monitored the lateral diffusion of lipid probes, DiIC(18)(3) and FAST DiI which are similar in their intrinsic fluorescence properties but differ in their structure, in native and cholesterol-depleted hippocampal membranes using the fluorescence recovery after photobleaching (FRAP) approach. Our results show that the mobility of these probes is in general higher in hippocampal membranes depleted of cholesterol. Interestingly, the increase in mobility of these probes does not linearly correlate with the extent of cholesterol depletion. These results assume significance in the light of recent reports on the requirement of cholesterol to support the function of the G-protein coupled serotonin(1A) receptor present endogenously in hippocampal membranes.

Animals↗

PubMed2006

Role of cholesterol in the function and organization of G-protein coupled receptors.

Cholesterol is an essential component of eukaryotic membranes and plays a crucial role in membrane organization, dynamics and function. The modulatory role of cholesterol in the function of a number of membrane proteins is well established. This effect has been proposed to occur either due to a specific molecular interaction between cholesterol and membrane proteins or due to alterations in the membrane physical properties induced by the presence of cholesterol. The contemporary view regarding heterogeneity in cholesterol distribution in membrane domains that sequester certain types of membrane proteins while excluding others has further contributed to its significance in membrane protein function. The seven transmembrane domain G-protein coupled receptors (GPCRs) are among the largest protein families in mammals and represent approximately 2% of the total proteins coded by the human genome. Signal transduction events mediated by this class of proteins are the primary means by which cells communicate with and respond to their external environment. GPCRs therefore represent major targets for the development of novel drug candidates in all clinical areas. In view of their importance in cellular signaling, the interaction of cholesterol with such receptors represents an important determinant in functional studies of such receptors. This review focuses on the effect of cholesterol on the membrane organization and function of GPCRs from a variety of sources, with an emphasis on the more contemporary role of cholesterol in maintaining a domain-like organization of such receptors on the cell surface. Importantly, the recently reported role of cholesterol in the function and organization of the neuronal serotonin(1A) receptor, a representative of the GPCR family which is present endogenously in the hippocampal region of the brain, will be highlighted.

Animals↗

PubMed1991

Effect of phospholipase C on cholesterol solubilization in model bile. A concanavalin A-binding nucleation-promoting factor from human gallbladder bile.

Human bile contains a phospholipase C activity. To examine its pathophysiological importance, the effect of phospholipase C on the dynamics of lipid solubilization and nucleation (cholesterol crystal formation) were investigated in model bile. Phospholipase C from gallbladder bile from patients with gallstones was partially purified by competitively eluting from a concanavalin A (con A)-Sepharose (Sigma, St. Louis, MO) column and incubating with Pronase (Calbiochem, Behring Diagnostics, La Jolla, CA). Phospholipase C activity was resistant to Pronase digestion. When this fraction (concentrated to half the original volume) was mixed with model bile (1:1, vol/vol), a transfer of cholesterol and phospholipid from the micellar to the vesicular phase and an accelerate nucleation time were found concomitant with phospholipid hydrolysis. These effects were prevented by inhibiting the phospholipase C activity with ethylenediaminetetraacetic acid. To confirm that the results were caused by phospholipase C activity and not some other nucleation-promoting factor within the biliary con A preparation, model bile was incubated with bacterial phospholipase C. An identical cascade of events to that found with the partially purified biliary enzyme was observed. Further purification of the con A-bound proteins on DEAE-Sephadex (Pharmacia, Uppsala, Sweden) did not resolve any separate nucleation-promoting activity to that associated with phospholipase C activity. In conclusion, this study has identified phospholipase C as a/the con A nucleation-promoting activity in human gallbladder bile and has characterized a possible molecular mechanism by which cholesterol nucleation is stimulated by this fraction.

Bile↗

PubMed2002

Effects of cholesterol on surface activity and surface topography of spread surfactant films.

Pulmonary surfactant forms a monolayer of lipids and proteins at the alveolar air/liquid interface. Although cholesterol is a natural component of surfactant, its function in surface dynamics is unclear. To further elucidate the role of cholesterol in surfactant, we used a captive bubble surfactometer (CBS) to measure surface activity of spread films containing dipalmitoylphosphatidylcholine/1-palmitoyl-2-oleoylphosphatidylcholine/1-palmitoyl-2-oleoylphosphatidylglycerol (DPPC/POPC/POPG, 50/30/20 molar percentages), surfactant protein B (SP-B, 0.75 mol %), and/or surfactant protein C (SP-C, 3 mol %) with up to 20 mol % cholesterol. A cholesterol concentration of 10 mol % was optimal for reaching and maintaining low surface tensions in SP-B-containing films but led to an increase in maximum surface tension in films containing SP-C. No effect of cholesterol on surface activity was found in films containing both SP-B and SP-C. Atomic force microscopy (AFM) was used, for the first time, to visualize the effect of cholesterol on topography of SP-B- and/or SP-C-containing films compressed to a surface tension of 22 mN/m. The protrusions found in the presence of cholesterol were homogeneously dispersed over the film, whereas in the absence of cholesterol the protrusions tended to be more clustered into network structures. A more homogeneous dispersion of surfactant lipid components may facilitate lipid insertion into the surfactant monolayer. Our data provide additional evidence that natural surfactant, containing SP-B and SP-C, is superior to surfactants lacking one of the components, and furthermore, this raises the possibility that the cholesterol found in surfactant of warm-blooded mammals does not have a function in surface activity.

Adsorption↗

PubMed1992

Pathophysiology and pharmacotherapy of cholelithiasis.

Several factors are involved in the development of gallstone formation: formation of supersaturated bile; nucleation; formation, retention and adhesion of cholesterol crystals and eventually stone growth. The dynamics of the gallbladder may play a key role in the overall process. The pathophysiologic theory of cholesterol gallstone formation and the knowledge of their physico-chemical properties support the modern concept of gallstone therapy. Chenodeoxycholic and ursodeoxycholic have been widely used as cholesterol gallstone dissolving agents and evaluated in terms of efficacy and safety.

Bile Acids and Salts↗

PubMed2001

Cholesterol effects on the phosphatidylcholine bilayer nonpolar region: a molecular simulation study.

A 15-ns molecular dynamics (MD) simulation of the fully hydrated dimyristoylphosphatidylcholine-cholesterol (DMPC-Chol) bilayer in the liquid-crystalline state was carried out to investigate the effect of Chol on the hydrocarbon chain region of the bilayer. The last 8-ns fragment of the generated trajectory was used for analyses. As a reference system, a pure DMPC bilayer (M. Pasenkiewicz-Gierula, Y. Takaoka, H. Miyagawa, K. Kitamura, and A. Kusumi, 1999, Biophys. J. 76:1228-1240) simulated for 14 ns was used. The study shows that a Chol-induced increase of the bulk molecular order parameter along both beta- and gamma-chain is mainly caused by a decrease of the average tilt of the chains, because the bulk average number of gauche rotamers/myristoyl chain is not significantly changed by Chol. Nevertheless, for DMPCs located near Chol molecules both the number of gauche rotamers/chain and the chain tilt are decreased. The magnitude of the Chol effect on the PC alkyl chains depends, in addition to the PC-Chol distance, on the side of the Chol molecule (alpha- or beta-face) that the chains are in contact with. This study provides some new insight into the properties of the coexistence region of the partial phase diagram for DMPC-Chol bilayers.

Cholesterol↗

PubMed2005

[Lipid lowering after percutaneous coronary intervention. Intended and achieved treatment goals in real life].

BACKGROUND: Dyslipidemia is associated with development and progression of coronary artery disease. Especially patients after coronary revascularization benefit by treatment with lipid-lowering drugs. Guidelines for lipid-lowering therapy in patients with or without coronary artery disease recommend treatment goals of lipid levels. However, relevant discrepancies between evidence-based goals and achieved lipid levels in "real life" are reported in large studies. METHODS AND RESULTS: In this study the dynamics of lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) and of lipid-lowering drugs were analyzed over a 5.5-month period in patients undergoing percutaneous coronary intervention. At the time of coronary intervention only 49.8% of patients were on lipid-lowering drugs, during follow-up dosage was modified only in exceptional cases. Although 87.5% of patients were treated at the time of follow-up, guideline-oriented lipid levels were achieved only in 32.5% of patients after 5.5 months. CONCLUSION: In a high-risk patient population after coronary revascularization, an ineffective treatment of hypercholesterolemia was found. A major problem is the lack of dosage modification of lipid-lowering drugs after initiation. By closer cooperation between hospital and general practitioner lipid-lowering treatment will be optimized and the rate of cardiovascular events will be decreased over long-term follow-up.

Aged↗

PubMed1999

Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.

OBJECTIVES: The study sought to determine the effects of lipid-lowering with pravastatin on the systemic fibrinolytic profile and on thrombus formation under dynamic flow conditions. BACKGROUND: Lowering cholesterol (C) decreases clinical events in coronary artery disease (CAD) patients, but an analysis of the effects of lipid-lowering on the entire hemostatic and thrombotic profile has not been conducted. METHODS: We prospectively studied 93 stable patients with untreated low-density lipoprotein cholesterol (LDL-C) >145 mg/dl. The CAD patients received pravastatin, and non-CAD patients were randomized to pravastatin versus placebo (double-blind). Thrombus formation upon an injured vascular surface was assessed in a substudy of 40 patients with a previously validated ex vivo perfusion chamber system. Systemic hemostatic markers and thrombus formation were evaluated at baseline, three and six months. RESULTS: Placebo produced no changes in either the lipid profile, any of the hemostatic markers, or the ex vivo thrombus formation. Both pravastatin groups (CAD and non-CAD) showed decreased LDL-C by 30% within 6 weeks (188 to 126 mg/dl, p < 0.001 vs. baseline), and decreased plasminogen activator inhibitor-1 at 3- and 6-month follow-up compared to baseline (15% to 18% decrease at 3 months and 21% to 23% at 6 months). For the tissue plasminogen activator antigen, CAD and non-CAD groups showed significant decreases at 6 months compared to baseline (10% and 13%, respectively). No significant changes were observed with treatment in d-dimer, fibrinopeptide A, prothrombin fragment F1.2, factor VIIa, von Willebrand factor, or C-reactive protein. Fibrinogen levels were significantly increased at 6 months compared to baseline, though still below the upper normal limit. In the perfusion chamber substudy, there was a decrease in thrombus area in non-CAD patients treated with pravastatin at both 3 and 6 months compared to baseline (by 21% and 34%, respectively). The CAD patients showed decreases in thrombus formation by 13% at 3 months, and by 16% at 6 months. The change in LDL-C- correlated modestly with the change in thrombus formation (r = 0.49; p < 0.01). CONCLUSIONS: Pravastatin therapy significantly decreased thrombus formation and improved the fibrinolytic profile in patients with and without CAD. These early effects may, in part, explain the benefit rendered in primary and secondary prevention of CAD.

Aged↗

PubMed1999

Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver.

Triglycerides are one of the most efficient storage forms of free energy. Because of their insolubility in biological fluids, their transport between cells and tissues requires that they be assembled into lipoprotein particles. Genetic disruption of the lipoprotein assembly/secretion pathway leads to several human disorders associated with malnutrition and developmental abnormalities. In contrast, patients displaying inappropriately high rates of lipoprotein production display increased risk for the development of atherosclerotic cardiovascular disease. Insights provided by diverse experimental approaches describe an elegant biological adaptation of basic chemical interactions required to overcome the thermodynamic dilemma of producing a stable emulsion vehicle for the transport and tissue targeting of triglycerides. The mammalian lipoprotein assembly/secretion pathway shows an absolute requirement for: (1) the unique amphipathic protein: apolipoprotein B, in a form that is sufficiently large to assemble a lipoprotein particle containing a neutral lipid core; and, (2) a lipid transfer protein (microsomal triglyceride transfer protein-MTP). In the endoplasmic reticulum apolipoprotein B has two distinct metabolic fates: (1) entrance into the lipoprotein assembly pathway within the lumen of the endoplasmic reticulum; or, (2) degradation in the cytoplasm by the ubiquitin-dependent proteasome. The destiny of apolipoprotein B is determined by the relative availability of individual lipids and level of expression of MTP. The dynamically varied expression of cholesterol-7alpha-hydroxylase indirectly influences the rate of lipid biosynthesis and the assembly and secretion lipoprotein particles by the liver.

Apolipoproteins B↗

PubMed1997

Functional rafts in cell membranes.

A new aspect of cell membrane structure is presented, based on the dynamic clustering of sphingolipids and cholesterol to form rafts that move within the fluid bilayer. It is proposed that these rafts function as platforms for the attachment of proteins when membranes are moved around inside the cell and during signal transduction.

Animals↗

PubMed2006

Lipid rafts: membrane triage centers.

Both biochemical and live cell imaging studies suggest the existence of lipid rafts, specialized membrane microdomains that promote interaction among signaling molecules. Although their composition is still poorly understood, these highly dynamic domains are enriched in cholesterol, sphingolipids, and particular groups of proteins. The mechanism(s) by which trafficking into or out of lipid rafts affects signaling remains unclear.

ErbB Receptors↗

PubMed2003

Flotillas of lipid rafts in transit amplifying cell-like keratinocytes.

Lipid rafts are dynamic membrane microdomains enriched in cholesterol and sphingolipids and are involved in the regulation of a variety of cellular processes, such as proliferation, apoptosis and cell motility. We have previously described that large lipid raft aggregates are readily detectable on cultured keratinocyte cell line HaCaT by staining with the fluorescein-tagged cholera toxin (CTx-FITC). In this paper we adopted this method for the detection of lipid rafts in human epidermis and keratinocytes in culture. Double labelling of showed the non-overlapping clusters of basal cells in human epidermis: CD29dimCTx-FITCbright cells in the deep rate ridges and CD29brightCTx-FITCdim cells at the tips of dermal papillae. A similar patchy, non-overlapping staining pattern was observed in cultured keratinocytes in vitro. CTx-FITCbright cells are mitotically active whereas a large proportion of CTx-FITCdim cells are quiescent. We conclude that the epidermal stem-like cells, previously shown to occupy the tips of dermal papillae and to exhibit high density of membrane beta1 integrin have a low content of lipid rafts. In contrast, the putative transit amplifying cells in deep rate ridges show enrichment in lipid rafts. Thus, lipid rafts may be a factor controlling the mitotic activity of epidermal keratinocytes and possibly the differentiation of stem cells into the transit amplifying cells.

Adult↗

PubMed2004

Lipid rafts in higher plant cells: purification and characterization of Triton X-100-insoluble microdomains from tobacco plasma membrane.

A large body of evidence from the past decade supports the existence of functional microdomains in membranes of animal and yeast cells, which play important roles in protein sorting, signal transduction, or infection by pathogens. They are based on the dynamic clustering of sphingolipids and cholesterol or ergosterol and are characterized by their insolubility, at low temperature, in nonionic detergents. Here we show that similar microdomains also exist in plant plasma membrane isolated from both tobacco leaves and BY2 cells. Tobacco lipid rafts were found to be greatly enriched in a sphingolipid, identified as glycosylceramide, as well as in a mixture of stigmasterol, sitosterol, 24-methylcholesterol, and cholesterol. Phospho- and glycoglycerolipids of the plasma membrane were largely excluded from lipid rafts. Membrane proteins were separated by one- and two-dimensional gel electrophoresis and identified by tandem mass spectrometry or use of specific antibody. The data clearly indicate that tobacco microdomains are able to recruit a specific set of the plasma membrane proteins and exclude others. We demonstrate the recruitment of the NADPH oxidase after elicitation by cryptogein and the presence of the small G protein NtRac5, a negative regulator of NADPH oxidase, in lipid rafts.

Blotting, Western↗

PubMed2002

Heat acclimation in rats: modulation via lipid polyunsaturation.

Heat acclimation of rats has been shown to enhance endurance of rat hearts to ischemic insult and acute heat stress. Common protective features have been shown to be operative during both these stress-inducing conditions. To explore the role of membrane lipid composition in the adaptive response, we analyzed two major parameters that impact membrane dynamics and order, the nonesterified cholesterol levels and the acyl chain composition of phospholipids, in rat heart and salivary glands, both major thermoregulatory organs, in short- and long-term heat-acclimated rats. Before exposure to heat, control salivary gland tissue has a higher cholesterol-to-phospholipid mole ratio (0.32 +/- 0.02) than heart (0.14 +/- 0.01), and the acyl chains of its phospholipids are 50% more saturated. The remodeling strategies of the tissues after exposure to heat differed. Heart cholesterol levels increased after short-term heat acclimation (approximately 50%), whereas salivary gland cholesterol levels decreased in acute heat stress and long-term heat acclimation (approximately 32%). Remodeling of phospholipid acyl chains, particularly an increase in docosahexaenoic acid, was a protective strategy in both tissues (57% in heart and >100% in salivary glands). Modifying membrane lipid composition by treating rats with liposomes composed of egg phosphatidylcholine (PC) before exposure to heat resulted in a 38% increase in endurance to thermal stress. The density and affinity of muscarinic receptors of submaxillary salivary glands, involved in the acclimation response, were measured in control and PC liposome-treated rats, and then both groups were subjected to short-term heat acclimation. After PC treatment the well-established compensatory upregulation of the muscarinic receptors and concomitant decrease in their affinity was blunted. The substantial increase in the thermal endurance of heat-challenged intact rats after treatment with PC liposomes (600 vs. 200 min) suggests that membrane lipid composition plays a role in the ability of these tissues to respond to heat stress.

Adaptation, Physiological↗