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Results for “Cholesterol dynamics”

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PubMed1990

[The effect of propranolol on the apoprotein spectrum of the blood plasma in patients with ischemic heart disease].

The authors studied the effect of anaprilin monotherapy (dose: 160-200 mg/daily for 10 months) on the level of atherogenic apolipoproteins (apo A, apo B) and fractions of plasma cholesterol in 34 patients with ischemic heart disease, stable exertion angina pectoris (class 2-3). It was established that changes in the plasma lipid and apoprotein spectrum result in an increase of apo B, decrease of apo 1, increase of apo B/apo A1, decrease of high-density lipoprotein cholesterol (HDLCS) and a different dynamics of HDLCS/apo A1. The established changes in the lipid metabolism are of atherogenic character.

Angina Pectoris↗

PubMed1994

Water transport across biological membranes.

The rate of the lateral diffusion of straight-chain phospholipids predicts the rate of water diffusion through bilayers. A new model of lipid dynamics integrates these processes. Substances such as cholesterol that reduce water diffusion proportionally reduce lateral diffusion. The model yields a number of predictions about the dynamics of the lipids at the Tm and suggests different mechanisms for how water diffuses across bilayers of other-than-straight-chain lipids, and how proteins bind to membranes. A second recent development in water transport across biological membranes is the discovery of a ubiquitous family of water transport proteins that facilitate large-volume water translocation. Like water diffusion through lipid bilayers, water transport by these proteins is directed by osmosis and is therefore under the control of ATP and ion pumps. The presence of water transport proteins in membranes is often regulated by hormones.

Biological Transport↗

PubMed2000

Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor.

Cholesterol entering cells in low-density lipoproteins (LDL) via receptor-mediated endocytosis is transported to organelles of the late endocytic pathway for degradation of the lipoprotein particles. The fate of the free cholesterol released remains poorly understood, however. Recent observations suggest that late-endosomal cholesterol sequestration is regulated by the dynamics of lysobisphosphatidic acid (LBPA)-rich membranes [1]. Genetic studies have pinpointed a protein, Niemann-Pick C-1 (NPC-1), that is required for the mobilization of late-endosomal/lysosomal cholesterol by an unknown mechanism [2]. Here, we report the removal of accumulated cholesterol by overexpression of the NPC-1 protein in NPC-1-deficient fibroblasts from patients with Niemann-Pick disease, and in normal fibroblasts upon release of a progesterone-induced block of cholesterol transport. We show that late-endosomal/lysosomal cholesterol mobilization is specifically inhibited by microinjection of Rab GDP-dissociation inhibitor (Rab-GDI). Moreover, clearance of the cholesterol deposits by NPC-1 in patients' fibroblasts is accompanied by the redistribution of LBPA and of a lysosomal hydrolase that utilizes the mannose-6-phosphate receptor. Our results reveal, for the first time, the involvement of a specific molecular component of the membrane-trafficking machinery in cholesterol transport and the coupling of late-endosomal cholesterol egress to the trafficking of other lipid and protein cargo.

Cell Line↗

PubMed2000

A (2)H NMR study of macroscopically aligned bilayer membranes containing interfacial hydroxyl residues.

The polar interface of membranes containing phosphatidylglycerol or cholesterol was studied by (2)H nuclear magnetic resonance (NMR) as a function of membrane hydration. The membranes were macroscopically aligned and hydrated with deuterium oxide. Water uptake and membrane annealing was achieved under NMR control, using a novel hydration technique. Well-resolved (2)H quadrupolar doublets were obtained from individual hydroxyl residues and from the interlamellar water. The response of the phosphatidylglycerol headgroup and of the cholesterol molecule to the spontaneous evaporation of interlamellar water could be thus monitored continuously. It is shown that the phosphatidylglycerol headgroup undergoes changes of conformation and average orientation with respect to the membrane surface and that the off-axis motion of the cholesterol molecule decreases. The deuteron exchange between hydroxyl residues and surface-associated D(2)O was determined by an inversion transfer technique. The exchange rates of the hydroxyl residues in the phosphatidylglycerol headgroup were different and depended strongly on the total hydration of the membrane. Significantly lower and almost hydration-independent rates were obtained for cholesterol. These results will be discussed with reference to earlier reports on the headgroup dynamics of phosphatidylglycerol and on the interaction of cholesterol with the membrane-water interface.

Biophysical Phenomena↗

PubMed2002

Cholesterol-induced modifications in lipid bilayers: a simulation study.

We present analysis of new configurational bias Monte Carlo and molecular dynamics simulation data for bilayers of dipalmitoyl phosphatidyl choline and cholesterol for dipalmitoyl phosphatidyl choline:cholesterol ratios of 24:1, 47:3, 11.5:1, 8:1, 7:1, 4:1, 3:1, 2:1, and 1:1, using long molecular dynamics runs and interspersed configurational bias Monte Carlo to ensure equilibration and enhance sampling. In all cases with cholesterol concentrations above 12.5% the area per molecule of the heterogeneous membrane varied linearly with cholesterol fraction. By extrapolation to pure cholesterol, we find the cross-sectional area of cholesterol in these mixtures is approximately 22.3 A(2). From the slope of the area/molecule relationship, we also find that the phospholipid in these mixtures is in a liquid ordered state with an average cross-sectional area per lipid of 50.7 A(2), slightly above the molecular area of a pure phospholipid gel. For lower concentrations of cholesterol, the molecular area rises above the straight line, indicating the "melting" of at least some of the phospholipid into a fluid state. Analysis of the lateral distribution of cholesterol molecules in the leaflets reveals peaks in radial distributions of cholesterols at multiples of approximately 5 A. These peaks grow in size as the simulation progresses, suggesting a tendency for small subunits of one lipid plus one cholesterol, hydrogen bonded together, to act as one composite particle, and perhaps to aggregate with other composites. Our results are consistent with experimentally observed effects of cholesterol, including the condensation effect of cholesterol in phospholipid monolayers and the tendency of cholesterol-rich domains to form in cholesterol-lipid bilayers. We are continuing to analyze this tendency on longer timescales and for larger bilayer patches.

Biophysical Phenomena↗

PubMed1976

The process of cholesterol cholelithiasis induced by diet in the prairie dog: a physicochemical characterization.

The rapid induction of cholesterol cholelithiasis in a new experimental model, the prairie dog, has recently been reported by two groups. In this model they were able to induce gallstones in as brief a period as 2 weeks, using a 1.2 per cent cholesterol diet. This unprecedented time intensity or telescoping of the induction process provided a unique opportunity for observation of physicochemical changes occurring rapidly over a short period of time and to correlate these with degree of biliary cholesterol saturation. To make such observations, 97 adult male and female prairie dogs were used in the present study. Seventy-two were fed the high cholesterol diet and sacrificed at intervals over a 14-day period; the remaining 25 were used as controls. The primary objective of this work was to determine whether or not there was any relationship between the in vivo events induced in prairie dog bile and our recently reported detailed observations of cholesterol precipitation phenomena in synthetic bile analogs. In these studies, solutions of physiologically relevant composition were constructed, which, when plotted according to convention on a tri-linear graph, fell within the zone of metastable or suspended supersaturation. These solutions revealed a consistent and previously undescribed liquid crystal to solid crystal phase transition during their approach to equilibrium at 37 degrees C. The in vivo studies of prairie dog bile following rapid induction of supersaturation revealed identical changes. At first, the supersaturated biles were isotropic followed by a period of turbidity and invariable formation of mesophase. After a few days, the liquid crystals decreased and solid cholesterol crystallites appeared. The most striking aspect of these observations is that the in vitro work has now predicted not only static, but dynamic processes as well, with respect to cholesterol precipitation beginning with the metastably supersaturated state and eventuating in gallstone formation. Ancillary new findings, resulting from the high cholesterol diet, included the induction of human-like hyper-beta-lipoproteinemia and rapid hepatocyte degranulation shown by electron microscopy.

Animals↗

PubMed1993

A 3D model of the peripheral benzodiazepine receptor and its implication in intra mitochondrial cholesterol transport.

A three-dimensional (3D) model of the peripheral benzodiazepine receptor (PBR) has been built using molecular dynamics simulations. The transmembrane domain of the receptor has been modeled as five alpha-helices, which are not long enough to cross the entire bilayer membrane but correspond approximately to only one phospholipid layer. The receptor model has also been tested as a cholesterol carrier, and molecular dynamics simulations have shown that it could indeed accommodate a cholesterol molecule within the five helices. All three known PBR sequences have been modeled, and no significant difference has been found between them.

Amino Acid Sequence↗

PubMed2001

On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells.

Evidence is accumulating for a link between cerebral cholesterol metabolism and Alzheimer's disease (AD). Here we focus on a possible relationship between AD and a newly discovered mechanism for cholesterol efflux from the brain, involving conversion of brain cholesterol into 24S-hydroxycholesterol by the neuronal oxidative enzyme CYP46. There was a marked difference in the distribution of CYP46 in brains of control and AD patients. The neuronal cells were less stained in AD brains than in controls while marked positive staining was found in glial cells in AD but not in controls. The dynamic changes in the mechanisms for cholesterol efflux from the brain are of interest in relation to the link between brain cholesterol and amyloid beta-protein in AD.

Aged↗

PubMed1993

[General topics in abnormalities of lipoprotein metabolism].

Level of plasma cholesterol and triglycerides are regulated by a dynamic equilibrium between diet-derived exogenous supply and endogenous synthesis and degradation. The metabolism of lipoproteins such as chylomicron, VLDL, IDL, LDL and HDL, carrying cholesterol and triglycerides is regulated strictly by specific apoprotein constituents of these lipoprotein classes and its receptors. In addition, the metabolism of chylomicron and VLDL is also regulated by lipoprotein lipase on the surface of arterial wall. Current knowledge of the processes of lipid transport, such as cholesterol and triglycerides in the blood owes much to discoveries of major gene mutations affecting the apoproteins, key enzymes that control lipid transport, and cellular receptors that recognize specific apoproteins. It is, indeed, difficult to imagine how this field (lipoprotein metabolism) could have reached its present state in the absence of discoveries, which resulted from many clinical investigations of patients manifesting abnormalities of the plasma lipoproteins. General topics in lipoprotein metabolism and its abnormalities are summarized here.

Humans↗

PubMed1982

[Effect of fluorine on development of experimental atherosclerosis].

A four-month experiment with rabbits was carried out, aiming at the elucidation of fluorine effect in the development of experimental hypercholesterolemia. The experimental animals were grouped into five groups: group I--control; group II--treated with 0,5 mg/kg cholesterol; group III--administered 10 MAC fluorine; group IV and V--treated with combination fluorine and cholesterol. The animals were monthly examined and the dynamics of body weight, total blood count were followed up as well as the biochemical indices/ total lipids, cholesterol, beta-lipoproteins, blood sugar, urea, uric acid and some electrolytes/. Femurs and teeth of the experimental animals were tested for fluorine content and dry substance in them. Pathoanatomical and histochemical investigations were also performed. The results obtained allow to admit that fluorine, as a mictoelement, plays a certain role in the inhibition of the development of the experimental hypercholesterolemia and atherosclerosis.

Animals↗

PubMed2005

MLN64 is involved in actin-mediated dynamics of late endocytic organelles.

MLN64 is a late endosomal cholesterol-binding membrane protein of an unknown function. Here, we show that MLN64 depletion results in the dispersion of late endocytic organelles to the cell periphery similarly as upon pharmacological actin disruption. The dispersed organelles in MLN64 knockdown cells exhibited decreased association with actin and the Arp2/3 complex subunit p34-Arc. MLN64 depletion was accompanied by impaired fusion of late endocytic organelles and delayed cargo degradation. MLN64 overexpression increased the number of actin and p34-Arc-positive patches on late endosomes, enhanced the fusion of late endocytic organelles in an actin-dependent manner, and stimulated the deposition of sterol in late endosomes harboring the protein. Overexpression of wild-type MLN64 was capable of rescuing the endosome dispersion in MLN64-depleted cells, whereas mutants of MLN64 defective in cholesterol binding were not, suggesting a functional connection between MLN64-mediated sterol transfer and actin-dependent late endosome dynamics. We propose that local sterol enrichment by MLN64 in the late endosomal membranes facilitates their association with actin, thereby governing actin-dependent fusion and degradative activity of late endocytic organelles.

Actins↗

PubMed2005

Electron paramagnetic resonance studies of magnetically aligned phospholipid bilayers utilizing a phospholipid spin label: the effect of cholesterol.

X-band EPR spectroscopy has been employed to study the dynamic properties of magnetically aligned phospholipid bilayers (bicelles) utilizing a variety of phosphocholine spin labels (n-PCSL) as a function of cholesterol content. The utilization of both perpendicular and parallel aligned bicelles in EPR spectroscopy provides a more detailed structural and orientational picture of the phospholipid bilayers. The magnetically aligned EPR spectra of the bicelles and the hyperfine splitting values reveal that the addition of cholesterol increases the phase transition temperature and alignment temperature of the DMPC/DHPC bicelles. The corresponding molecular order parameter, Smol, of the DMPC/DHPC bicelles increased upon addition of cholesterol. Cholesterol also decreased the rotational motion and increased the degree of anisotropy in the interior region of the bicelles. This report reveals that the dynamic properties of DMPC/DHPC bicelles agree well with other model membrane systems and that the magnetically aligned bicelles are an excellent model membrane system.

Cholesterol↗

PubMed1994

[Effect of Chinese herbal preparation on major constituents of bile of gallstones patients].

From 1991 to 1993, 51 patients in 3 groups who had received biliary operation with T tube drainage were selected for observation of dynamic change in bile acid, bilirubin, cholesterol and mucin in the bile within 3 days after taking the Danyihewei granule (DYHW) and Rongshisan (RSS). Result showed that in DYHW group the bile acid increased significantly on the 2nd and 3rd day (P < 0.01), along with significant lowering of bilirubin (P < 0.01) and mucin (P < 0.05, P < 0.01) in 1st through 3rd day. In the RSS group the bile acid remarkably increased on the 3rd day (P < 0.05) with significant reduction of bilirubin (P < 0.01) on 2nd and 3rd day. The control group showed no remarkable change. The bile acid/bilirubin and bile acid/cholesterol ratios all had a dynamic increase with 3 days in treated group. Whereas the control group remained unchanged. Therefore the DYHW and RSS were able to produce a strong inhibitory effect on stone-forming bile through regulation of liver and discharge of bile.

Adolescent↗

PubMed2001

Health effects resulting from exercise versus those from body fat loss.

OBJECTIVE: The purpose of this review was to assess whether body weight confounds the relationships between physical activity and its health benefits. METHODS: The review includes 80 reports from population-based studies (Evidence Category C) of physical activity or fitness and cardiovascular disease (CVD) or coronary heart disease (CHD). RESULTS: Eleven of 64 reports on activity found no relationship between physical activity and disease. Of the remaining 53 reports, 11 did not address the possible confounding effects of body weight, nine cited reasons that weight differences should not explain their observed associations, and 33 statistically adjusted for weight (as required). Only three of these changed their associations from significant to nonsignificant when adjusted. Ten of 16 reports on cardiorespiratory fitness and CHD or CVD used statistical adjustment, and none of these changed their findings to nonsignificant. Population studies show that vigorously active individuals also have higher high-density lipoprotein (HDL)-cholesterol concentration, a major risk factor for CHD and CVD, than sedentary individuals when statistically adjusted for weight. In contrast, intervention studies, which relate dynamic changes in weight and HDL, suggest that adjustment for weight loss largely eliminates the increase in HDL-cholesterol in sedentary men who begin exercising vigorously. Adjusting the cross-sectional HDL-cholesterol differences for the dynamic effects of weight loss eliminates most of the HDL-cholesterol difference between active and sedentary men. CONCLUSION: Population studies show that the lower incidence of CHD and CVD and higher HDL of fit, active individuals are not because of lean, healthy individuals choosing to be active (i.e., self-selection bias). Nevertheless, metabolic processed associated weight loss may be primarily responsible for the HDL differences between active and sedentary men, and possibly also their differences in CHD and CVD.

Adipose Tissue↗

PubMed1999

Size distributions of chylomicrons from human lymph from dynamic light scattering measurements.

Chylomicrons, the vehicles for the transport of exogeneous triglycerides and cholesterol in the lymph and the blood, were characterized by their size from dynamic light scattering measurements. To achieve an appropriate resolution, correlation data were collected over several hours. Analysis was performed with an extended version of the regularization method CONTIN, and special attention was given to errors in the experimental baseline and to randomness of the residuals. The solutions selected by means of Fisher's F-test by CONTIN agreed with those obtained with the stability plot of Schnablegger and Glatter, when in the case of data of lower statistical accuracy the solution was taken from the lower part of the confidence interval of the F-test. The intensity-weighted size distributions indicated two classes of particle, their mean diameters being 100-140 nm and 330-350 nm. The ability to resolve two peaks of such a size ratio is demonstrated. The numbers of particles associated with the two peaks were estimated by means of the scattering properties of the particles, which showed that the overwhelming majority were small ones. This estimation also suggested that the mean size of the first peak of the number distribution is significantly smaller than the typical size of chylomicrons. This was consistent with the finding that the sample contained not only apolipoprotein B-48 but also a similar amount of apolipoprotein B-100, which is associated with lipoproteins of smaller size. The larger particles of the second peak are probably dietary triglyceride-rich chylomicrons.

Algorithms↗

PubMed2004

Complexation of phosphatidylcholine lipids with cholesterol.

It is postulated that the specific interactions between cholesterol and lipids in biological membranes are crucial in the formation of complexes leading subsequently to membrane domains (so-called rafts). These interactions are studied in molecular dynamics simulations performed on a dipalmitoylphosphatidylcholine (DPPC)-cholesterol bilayer mixture and a dilauroylphosphatidylcholine (DLPC)-cholesterol bilayer mixture, both having a cholesterol concentration of 40 mol %. Complexation of the simulated phospholipids with cholesterol is observed and visualized, exhibiting 2:1 and 1:1 stoichiometries. The most popular complex is found to be 1:1 in the case of DLPC, whereas the DPPC system carries a larger population of 2:1 complexes. This difference in the observed populations of complexes is shown to be a result of differences in packing geometry and phospholipid conformation due to the differing tail length of the two phosphatidylcholine lipids. Furthermore, aggregation of these complexes appears to form hydrogen-bonded networks in the system containing a mixture of cholesterol and DPPC. The CH...O hydrogen bond plays a crucial role in the formation of these complexes as well as the hydrogen bonded aggregates. The aggregation and extension of such a network implies a possible means by which phospholipid:cholesterol domains form.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1991

Dynamics of the bilayer-water interface of phospholipid vesicles and the effect of cholesterol: a picosecond fluorescence anisotropy study.

The motion of the head group of phospholipid molecules in the bilayer structure was investigated by a picosecond fluorescence anisotropy technique using a newly synthesized fluorescent phospholipid, dipalmitoyl-L-alpha-phosphatidyl-(3-p-methoxyphenyl)umbelliferone (DPPU). In this phospholipid, a coumarin derivative is attached covalently to the phosphate moiety. The motion of the acyl chain of the phospholipid was also investigated by the same method using 1-palmitoyl-2-(3-diphenylhexatrienyl)-propanoyl-L-alpha-phospha tid ylcholine (DPHpPC). From fluorescence anisotropy decay the wobbling diffusion rate (Dw) of DPPU and DPHpPC in DPPC vesicles at 45 degrees C was calculated to be 2.7 x 10(9) s-1 and 5.1 x 10(7) s-1 using the wobbling-in-cone-model. The range of the motion was calculated as the cone angle (theta c), which is half of the angle of the cone in which the fluorophore can diffuse. The cone angle of the coumarin skeleton of DPPU in DPPC vesicles at 45 degrees C was 64 degrees, which was larger than that of the DPH skeleton of DPHpPC, 40 degrees. These results indicate that the motion of the head group is much faster and wider than that of the acyl chain. When cholesterol was added to the DPPC vesicles, the range of motion of the acyl chain decreased, but that of the head group increased. These facts show that cholesterol restricts the motion of the acyl chain but enhances that of the head group in the phospholipid bilayer.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1999

Effect of mild hyperlipidaemia on testicular cell population dynamics in albino rats.

Mild hyperlipidaemia induced by cholesterol feeding to male rats altered testicular histology. The sperm motility and density were significantly reduced in cauda epididymides and testes in mild hyperlipidaemic rats. The testicular cell population i.e. spermatocytes (primary and secondary) and spermatids were significantly reduced (P < or = 0.01 to 0.001). However, the number of degenerating Leydig cells (interstitial cells) were increased significantly (P < or = 0.001). Serum biochemistry reveals significant rise in cholesterol and triglycerides. It is concluded that cholesterol feeding caused inhibition of spermato genesis.

Animals↗