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PubMedDate not supplied

In vitro cultivation of mycobacteria in cholesterol lecithin media from lepromas of rats infected with Mycobacterium lepraemurium.

In vivo grown M. lepraemurium suspensions were inoculated into a basal medium containing cholesterol and lecithin. Slow growing strains of mycobacteria were cultured regularly in these media. The presence of free cholesterol or cholesterol in serum or cholesterol in trypsin-digested egg yolk was essential for growth. The primary cultures were difficult to obtain, but the strains were easily subcultured. A heavy inoculum was necessary to obtain primary cultures in the liquid media, no growth occurred on semisolid agar slants. Similarly slow-growing primary cultures were obtained on Ogawa egg yolk media. Growth developed in a considerably shorter time if Ogawa's medium was enriched with 0.4% yeast extract (Difco). The cultures obtained on Ogawa egg yolk media were successfully subcultered in liquid cholesterol-lecithin media. The relation of the cultured strains of mycobacteria to the pathology of murine leprosy is not yet clear. The dynamics of cholesterol metabolism in the macrophages related to murine leprosy is discussed.

Animals↗

PubMed2004

A case follow-up report: possible health benefits of extra virgin olive oil.

In the course of a case study, a number of issues regarding the dynamics of blood cholesterol levels were identified. In this follow-up report, these issues are addressed. For example, issues of past behaviour and seasonality, intraindividual variation, and nonstationarity appear important over and above controllable variables such as diet and exercise. In this report, we conceptualise an alternative protective role for the dynamic blood cholesterol levels in a healthy population. Furthermore, regular consumption of extra virgin olive oil as produced in this case study may interact with the dynamics of cholesterol naturally. We recommend that future studies of this kind ought to include a time series of blood cholesterol based on daily measurements or intervals much shorter than the bimonthly measurements and to include measures of overall well being as covariates.

Follow-Up Studies↗

PubMed1992

Cholesterol in model membranes. A molecular dynamics simulation.

Molecular dynamics simulations of a model membrane with inserted cholesterol molecules have been performed to study the perturbing influence of cholesterol. In the fluid phase of a lipid bilayer at 13 mol% concentration of cholesterol, local ordering of the hydrocarbon chains is induced. This perturbation decays with the distance from the cholesterol, and the effect extends 1.25 nm. It can be monitored in several ways, e.g., by an order parameter corresponding to deuterium nuclear magnetic resonance quadrupolar splittings, by the fraction of gauche bonds, or by the local bilayer thickness. At constant surface density, the local ordering is accompanied by disordering of the bulk phase, and, consequently, the net ordering effect is small. After compressing the system laterally in accordance with experimentally known surface areas, the bulk order parameters agree with those of a pure system, and the average order parameters are in accordance with experimental data. The necessity for this lateral compression is supported by calculated lateral pressures. At lower cholesterol concentration (3%), no direct perturbing effect is observed. A smaller lateral pressure than in a pure system indicates that the system with cholesterol is expected to have a smaller surface area, which would result in an increase of the order parameters, thus accounting for the experimental observations. The lack of spatial variation is, however, puzzling and may indicate a cooperative ordering effect.

Cholesterol↗

PubMed1986

Atherosclerosis and lipoprotein metabolism: role of reverse cholesterol transport.

To understand the complexity of lipoprotein metabolism and its influence on atherosclerosis, one must be aware of the physiologic characteristics and functions of the different lipoprotein classes, apolipoproteins and enzymes. Understanding of the dynamics of cholesterol and lipoprotein metabolism, especially reverse cholesterol transport, will aid in finding a means of preventing and reversing the atherosclerotic process.

Apolipoproteins↗

PubMed2000

Regulation of receptor function by cholesterol.

Cholesterol influences many of the biophysical properties of membranes and is nonrandomly distributed between cellular organelles, subdomains of membranes, and leaflets of the membrane bilayer. In combination with the high dynamics of cholesterol distribution, this offers many possibilities for regulation of membrane-embedded receptors. Depending on the receptor, cholesterol can have a strong influence on the affinity state, on the binding capacity, and on signal transduction. Most important, cholesterol may stabilize receptors in defined conformations related to their biological functions. This may occur by direct molecular interaction between cholesterol and receptors. In this review, we discuss the functional dependence of the nicotinic acetylcholine receptor as well as different G protein-coupled receptors on the presence of cholesterol.

Animals↗

PubMed2006

A FRET analysis to unravel the role of cholesterol in Rac1 and PI 3-kinase activation in the InlB/Met signalling pathway.

The signalling pathway for the hepatocyte growth factor receptor, Met/HGF-R, is hijacked by the bacterial surface protein InlB to induce Listeria monocytogenes entry into non-phagocytic cells. We previously showed that Listeria invades host cells by interacting with specialized microdomains of the host plasma membrane called lipid rafts. In this study, we analysed in living cells signalling events that are crucial for Listeria entry using a fluorescence resonance energy transfer-based microscopic method. Phosphoinositide (PI) 3-kinase activity and Rac1 signalling induced by Listeria interacting with epithelial cells were monitored as well as signalling induced by soluble InlB and the Met natural ligand HGF. We found that InlB and HGF induced similar kinetics of PI 3-kinase and Rac1 activation. PI 3-kinase activation was upstream and independent of Rac1 activation. Cholesterol-depletion experiments were performed to address the role of lipid rafts in Met signalling. The amount of 3'-phosphoinositides produced by PI 3-kinase was not affected by cholesterol depletion, while their membrane dynamic was cholesterol-dependent. Rac1 activation, downstream from PI 3-kinase, was cholesterol-dependent suggesting that the spatial distribution of 3'-phosphoinositides within membrane microdomains is critical for Rac1 activation and consequently for F-actin assembly at bacterial entry site.

Animals↗

PubMed1993

Cholesterol cell content affects prolactin but not growth hormone release in GH4C1 cells.

It is generally accepted that cholesterol affects dynamic membrane properties and the function of membrane bound proteins involved in secretion processes. In the present study we employed GH4C1 cells treated with human lipoprotein-deficient serum (h-LPDS), exogenous cholesterol and high density lipoprotein (HDL3) to investigate the role of cholesterol cell content on PRL and GH basal release. Incubation of GH4C1 cells with h-LPDS decreased free cholesterol content and cholesterol added to the media increased it. HDL3 did not act as a cholesterol acceptor in either cholesterol-depleted or cholesterol-loaded cells; however, in depleted cells HDL3 was a net donor, significantly increasing cell cholesterol. Control or cholesterol loaded cells incubated in media with h-LPDS increased their secretion of PRL in parallel with the loss of cell cholesterol. Conversely, the addition of either cholesterol or HDL3 to cholesterol depleted cells inhibited PRL release. However, GH secretion was not modified by changes in free cholesterol in any of these situations. In the experiments in which HDL3 was present, a highly positive correlation was found between cholesterol cell content at the end of the experiment and PRL secretion, no effect could be related to the amount of added HDL3, suggesting that the HDL3 had no specific effect on the secretion of PRL or GH. Our results indicate that cholesterol cell content is an important factor in the release of PRL but not of GH, and emphasize the differences in the basal regulation of the secretion of both hormones.

Cell Line↗

PubMed2006

Modulation of amphotericin B membrane interaction by cholesterol and ergosterol--a molecular dynamics study.

Amphotericin B (AmB) is a well-known polyene macrolide antibiotic used to treat systemic fungal infections. According to a well-documented hypothesis, molecules of AmB form ionic membrane channels that are responsible for chemotherapeutic action. These channels disturb the barrier function of the cell membrane which, in consequence, leads to cell death. The presence of sterols in the cell membrane is necessary for full manifestation of the antibiotic's ionophoric activity, at least in vivo. Ergosterol-containing fungal membranes are targeted more efficiently by AmB than mammalian membranes containing cholesterol. However, a similar level of disturbance of fungal and mammalian membranes is responsible for serious toxicity of the antibiotic. Due to the importance of AmB and lack of better antifungal alternatives, the search for new less toxic derivatives of this antibiotic still continues. Therefore, studies of the AmB-membrane interaction are very important. The present work constitutes a continuation of a broad program of study on AmB mode of action in our group. In particular, molecular dynamics simulations of AmB monomers inside the bilayers of three different compositions (pure dimiristoylphosphatidylcholine (DMPC) and DMPC bilayer containing approximately 25 mol % of cholesterol or ergosterol) were carried out. In general, analysis of generated trajectories resulted in identifying many significant differences in the behavior of AmB monomers depending on the membrane environment. In particular, it was established that the antibiotic increases the internal order of DMPC bilayer containing 25 mol % of cholesterol, while it has no effect on the order of the bilayer with the same amount of ergosterol. Performed calculations also revealed that relatively rigid and elongated AmB molecules exhibit higher affinity toward the sterol-containing lo phases and, therefore, may be cumulated in ordered membrane domains (e.g., lipid rafts). Since the partition coefficient between the ld and lo phase appears to be greater in the case of the ergosterol- compared to cholesterol-containing membrane, this effect can be also discussed as the possible origin of AmB-selective toxicity and indirect sterol involvement in expression of AmB activity.

Amphotericin B↗

PubMed1976

[Regulation of cholesterol levels in plasma and liver of adult rats].

The dynamics of cholesterol-system in the plasma is characterized by a parameter which is a linear function of the internal secretion of cholesterol. So, the level of plasma cholesterol from synthesis is a low as its flow is high. Moreover, the level of plasma cholesterol from diet is simultaneously proportional to the flow of cholesterol intestinal absorption and dependent on the dynamics controlled by the internal secretion. The laws of the cholesterolemia cumulate these partial laws. Similar relations concern the esterified cholesterol in the liver.

Animals↗

PubMed2001

Molecular dynamics simulation of the structure of dimyristoylphosphatidylcholine bilayers with cholesterol, ergosterol, and lanosterol.

Five molecular dynamics computer simulations were performed on different phospholipid:sterol membrane systems in order to study the influence of sterol structure on membrane properties. Three of these simulated bilayer systems were composed of a 1:8 sterol:phospholipid ratio, each of which employed one of the sterol molecules: cholesterol, ergosterol, and lanosterol. The two other simulations were of a bilayer with a 1:1 sterol:phospholipid ratio. These simulations employed cholesterol and lanosterol, respectively, as their sterol components. The observed differences in simulations with cholesterol and lanosterol may have their implication on the form of the phospholipid/sterol phase diagram.

Carbon↗

PubMed2002

Comparative molecular dynamics simulations of amphotericin B-cholesterol/ergosterol membrane channels.

Amphotericin B (AmB) is a very effective anti-fungal polyene macrolide antibiotic whose usage is limited by its toxicity. Lack of a complete understanding of AmB's molecular mechanism has impeded attempts to design less toxic AmB derivatives. The antibiotic is known to interact with sterols present in the cell membrane to form ion channels that disrupt membrane function. The slightly higher affinity of AmB toward ergosterol (dominant sterol in fungal cells) than cholesterol (mammalian sterol) is regarded as the most essential factor on which antifungal chemotherapy is based. To study these differences at the molecular level, two realistic model membrane channels containing molecules of AmB, sterol (cholesterol or ergosterol), phospholipid, and water were studied by molecular dynamics (MD) simulations. Comparative analysis of the simulation data revealed that the sterol type has noticeable effect on the properties of AmB membrane channels. In addition to having a larger size, the AmB channel in the ergosterol-containing membrane has a more pronounced pattern of intermolecular hydrogen bonds. The interaction between the antibiotic and ergosterol is more specific than between the antibiotic and cholesterol. These observed differences suggest that the channel in the ergosterol-containing membrane is more stable and, due to its larger size, would have a higher ion conductance. These observations are in agreement with experiments.

Amphotericin B↗

PubMed1987

Structure and dynamics of plasmalogen model membranes containing cholesterol: a deuterium NMR study.

Deuterium nuclear magnetic resonance (2H-NMR) was used to investigate the structure and dynamics of the sn-2 hydrocarbon chain of semi-synthetical choline and ethanolamine plasmalogen in bilayers containing 0, 30, and 50 mol% cholesterol. The deuterium NMR spectra of the choline plasmalogen yielded well-resolved quadrupolar splittings which could be assigned to the corresponding hydrocarbon chain deuterons. The sn-2 acyl chain was found to adopt a similar conformation as observed in the corresponding diacyl phospholipid, however, the flexibility at the level of the C-2 methylene segment of the plasmalogen was increased. Deuterium NMR spectra of bilayers composed of the ethanolamine plasmalogen yielded quadrupolar splittings of the C-2 segment much larger than those of the corresponding diacyl lipids, suggesting that the sn-2 chain is oriented perpendicular to the membrane surface at all segments. Cholesterol increased the ordering of the choline plasmalogen acyl chain to the same extent as in diacyl lipid bilayers. T1 relaxation time measurements demonstrated only minor dynamical differences between choline plasmalogen and diacyl lipids in model membranes.

Cholesterol↗

PubMedDate not supplied

Lipid changes and statins in chronic renal insufficiency and dialysis.

Chronic renal failure patients suffer from a secondary form of complex dyslipidemia, similar to the so-called atherogenic dyslipidemia in insulin resistant patients or to diabetic dyslipidemia. The most important abnormalities are an increase in the serum level of triglyceride (elevated VLDL-remnants/IDL), small LDL particles and a low HDL cholesterol. The highly atherogenic LDL subclass, namely LDL-6 or small dense LDL, accumulates in hypertriglyceridemic diabetic hemodialysis patients. All these lipoprotein particles contain apoB, thus much of this complex disorder can be summarized as an elevation of triglyceride-rich apoB containing complex lipoprotein particles. Growing evidence suggests that all of the components of this type of dyslipidemia are independently atherogenic. Further disturbances exist in the dynamics of cholesterol exchange between the various lipoprotein particles and in transport from cells to catabolic sites. The European Joint Task Force and the US National Cholesterol Education Program expert panel have issued guidelines for the general population to lower the cardiovascular risk in hyper- and dyslipidemias. There is preliminary consensus that these guidelines should be applied to dialysis patients. However, the genesis of atherosclerosis in the dialysis population may be different and real benefit from lipid-lowering has not yet been demonstrated in this population. Large-scale, prospective randomized trials (4D-trial, HARP) are underway to determine whether statins reduce cardiovascular complications in diabetic and non-diabetic patients with end-stage renal disease (ESRD) and on hemodialysis treatment.

Humans↗

PubMed2005

Cholesterol and fatty acids regulate dynamic caveolin trafficking through the Golgi complex and between the cell surface and lipid bodies.

Caveolins are a crucial component of plasma membrane (PM) caveolae but have also been localized to intracellular compartments, including the Golgi complex and lipid bodies. Mutant caveolins associated with human disease show aberrant trafficking to the PM and Golgi accumulation. We now show that the Golgi pool of mainly newly synthesized protein is detergent-soluble and predominantly in a monomeric state, in contrast to the surface pool. Caveolin at the PM is not recognized by specific caveolin antibodies unless PM cholesterol is depleted. Exit from the Golgi complex of wild-type caveolin-1 or -3, but not vesicular stomatitis virus-G protein, is modulated by changing cellular cholesterol levels. In contrast, a muscular dystrophy-associated mutant of caveolin-3, Cav3P104L, showed increased accumulation in the Golgi complex upon cholesterol treatment. In addition, we demonstrate that in response to fatty acid treatment caveolin can follow a previously undescribed pathway from the PM to lipid bodies and can move from lipid bodies to the PM in response to removal of fatty acids. The results suggest that cholesterol is a rate-limiting component for caveolin trafficking. Changes in caveolin flux through the exocytic pathway can therefore be an indicator of cellular cholesterol and fatty acid levels.

Animals↗

PubMed1999

Membrane microdomains and caveolae.

Glycosphingolipid- and cholesterol-enriched microdomains, or rafts, within the plasma membrane of eukaryotic cells have been implicated in many important cellular processes, such as polarized sorting of apical membrane proteins in epithelial cells and signal transduction. Until recently, however, the existence of such domains remained controversial. The past year has brought compelling evidence that microdomains indeed exist in living cells. In addition, several recent papers have suggested that caveolae, which are considered to be a specific form of raft, and caveolins, the major membrane proteins of caveolae, are involved in the dynamic cholesterol-dependent regulation of specific signal transduction pathways.

Alzheimer Disease↗

PubMed1981

Importance of cholesterol-phospholipid interaction in determining dynamics of normal and abetalipoproteinemia red blood cell membrane.

Acanthocytic red blood cells in patients with abetalipoproteinemia have a decrease membrane fluidity that is associated with increased sphingomyelin/phosphatidylcholine (SM/PC) ratios. Here we describe studies designed to gain better insight into (i) the interrelationship between the composition of lipoprotein and red blood cell membrane in abetalipoproteinemia patients and normal controls; and (ii) how the differences in lipid composition of the red blood cell membrane affect its fluidity. The increased SM/PC ratio found in abetalipoproteinemia plasma high density lipoproteins (HDL) (3 times greater than controls) was paralleled by an increase in this ratio in acanthocytic red cells, but to a lesser degree (almost twice greater than control red cells). Cholesterol/phospholipid mole ratios (C/P) were increased 3-fold in abetalipoproteinemia HDL, but only slightly increased in red cells compared to controls values. As in the controls, 80-85% of abetalipoproteinemia red cell sphingomyelin was found to be in the outer half of the erythrocyte membrane. Membrane fluidity was defined in terms of microviscosity (eta) between 5 and 42 degrees C by the fluorescent polarization of 1,6-diphenylhexatriene (DPH) present in erythrocyte ghost membranes. At all temperatures, membrane microviscosity was higher in abetalipoproteinemia ghosts than controls, but these differences decreased at higher temperatures (12.34 vs 9.79 poise, respectively at 10 degrees C; 4.63 vs 4.04 poise at 37 degrees C). These differences were eliminated after oxidation of all membrane cholesterol to cholest-4-en-3-one by incubation with cholesterol oxidase. Following cholesterol oxidation, the membrane microviscosity decreased in patient ghosts more than in normal red blood cells so that at all temperatures no significant differences were present relative to control ghosts, in which the apparent microviscosity was also diminished but to a lesser degree. Therefore, although increased SM/PC ratios in abetalipoproteinemia may be responsible for decreased erythrocyte membrane fluidity, these effects are dependent upon normal interactions of cholesterol with red cell phospholipid.

Abetalipoproteinemia↗

PubMed1995

The composition and function of reptilian pulmonary surfactant.

In mammals, the surface tension of the fluid lining the inner lung greatly contributes to the work of breathing. Surface tension is modified by the secretion of a mixture of surface active lipids and proteins (termed pulmonary surfactant). A disaturated phospholipid (DSP), predominantly dipalmitoylphosphatidylcholine (DPPC), can eliminate surface tension under high dynamic compression. Cholesterol (CHOL) and unsaturated phospholipids (USP) promote respreading upon inflation by converting DPPC to the disordered liquid-crystalline state. It appeared to us that a surfactant rich in DPPC, which has a high phase transition temperature of 41 degrees C, is likely to be of only limited use in the lungs of reptiles, many of which have preferred body temperatures between 20 and 30 degrees C. We review here the presence and composition of surfactant in species from the three subclasses of the Reptilia and relate these to lung structure and function, phylogeny and environmental selection pressures such as body temperature. We also discuss the function of reptilian surfactant and the factors which control surfactant turnover. Large amounts of pulmonary surfactant have been found in all reptiles so far examined. In general, warmer reptiles have greater amounts of surfactant which is also relatively enriched in DSP. Cold lizards (18 degrees C) have significantly elevated levels of surfactant cholesterol. As in all vertebrates, PC is always the dominant phospholipid (60-80%). Unlike mammals, phosphatidylglycerol (PG) is absent, with the exception of one species. The remaining phospholipid groups are present to varying degrees. The saturated fatty acid, palmitic acid (16:0) is the dominant acyl group, oleic acid (18:1) is the dominant mono-unsaturated fatty acid, and polyunsaturates comprise only about 20% of the total fatty acid profile. For two species of dragon lizards, short term changes in temperature do not affect the fatty acids, but protracted periods of cold significantly decrease the presence of 16:0 in turtle lavage (Lau and Keough, Can.J. Biochem. 59: 208-219, 1981). Surfactant appears to function as an antiglue in most reptiles, serving to lower opening pressure, and decrease the work of breathing. However, surface tension forces generally do not influence reptilian lung compliance, suggesting that the primary functions of mammalian surfactant are not necessarily relevant to reptiles.

Animals↗

PubMed2004

Dynamic reorganization of chemokine receptors, cholesterol, lipid rafts, and adhesion molecules to sites of CD4 engagement.

T cell polarization and redistribution of cellular components are critical to processes such as activation, migration, and potentially HIV infection. Here, we investigate the effects of CD4 engagement on the redistribution and localization of chemokine receptors, CXCR4 and CCR5, adhesion molecules, and lipid raft components including cholesterol, GM1, and glycosyl-phosphatidylinositol (GPI)-anchored proteins. We demonstrate that anti-CD4-coated beads (alpha CD4-B) rapidly induce co-capping of chemokine receptors as well as GPI-anchored proteins and adhesion molecules with membrane cholesterol and lipid rafts on human T cell lines and primary T cells to the area of bead-cell contact. This process was dependent on the presence of cellular cholesterol, cytoskeletal reorganization, and lck signaling. Lck-deficient JCaM 1.6 cells failed to cap CXCR4 or lipid rafts to alpha CD4-B. Biochemical analysis reveals that CXCR4 and LFA-1 are recruited to lipid rafts upon CD4 but not CD45 engagement. Furthermore, we also demonstrate T cell capping of both lipid rafts and chemokine receptors at sites of contact with HIV-infected cells, despite the binding of an HIV inhibitory mAb to CXCR4. We conclude that cell surface rearrangements in response to CD4 engagement may serve as a means to enhance cell-to-cell signaling at the immunological synapse and modulate chemokine responsiveness, as well as facilitate HIV entry and expansion by synaptic transmission.

CD4 Antigens↗