The dynamics of erythrocyte membrane cholesterol.
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Abetalipoproteinemia↗
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The influence of chenodeoxycholic acid on cholesterol and bile acid turnover in humans with cholelithiasis.
The in vivo dynamics of cholesterol were determined in 8 individuals who were part of a national double-blind study testing the efficacy of chenodeoxycholic acid ingestion on the dissolution of gallstones. Despite the ingestion of this bile acid in amounts in excess of its normal endogenous flux, the conversion of neutral sterol to chenodeoxycholic acid continued. The flux of neutral sterol to endogenous chenodeoxycholate was lower for the patients ingesting bile acid than for one of the patients on placebo, but was similar to that of the other control and similar to previously published chenodeoxycholate flux in patients with cholesterol cholelithiasis. The remaining flux was on the basis of the very efficiently absorbed dietary chenodeoxycholate. The total cholesterol fractional catabolic rate and flux were not appreciably diminished by the administration of either high or low dose chenodeoxycholate to these individuals with cholesterol cholelithiasis.
Adult↗
Cholesterol flux between high density lipoproteins and cultured rat luteal cells.
Although high density lipoprotein (HDL) is a promoter of cholesterol efflux from peripheral cells, in steroidogenic tissues it has been shown to provide cholesterol for steroid synthesis. The present study examines the dynamics of cholesterol exchange between HDL particles and rat luteal cells. Cholesterol influx was measured by following the uptake of label from HDL particles labeled with [3H]cholesterol or [3H]cholesteryl linoleate. The efflux of cholesterol was simultaneously measured by incubating [3H]cholesterol-labeled luteal cells with unlabeled HDL. Conversion of endogenous and lipoprotein-derived steroids to progestins was also determined. The results showed that HDL promotes both influx and efflux of cholesterol in those cells. The amount of influx exceeds efflux, thus resulting in a net uptake of cholesterol from HDL by rat luteal cells. The relative utilization of endogenous vs. HDL-derived cholesterol for steroid synthesis was also examined. The results show that only a fraction of the HDL-derived cholesterol was converted directly to steroids. The fraction that was converted depended on the HDL concentration and had no apparent relation to the incubation time. These results show that although cholesterol flux in luteal cells is bidirectional in the presence of HDL, the influx exceeds the amount of efflux, and the internalized cholesterol is diluted with the endogenous cholesterol pool before it is converted to steroids.
Animals↗
Molecular dynamics simulations of SOPS and sphingomyelin bilayers containing cholesterol.
We performed a molecular dynamics simulation of an asymmetric bilayer that contained different lipid mixtures in its outer and inner leaflets. The outer leaflet contained a mixture of sphingomyelin (SM) with cholesterol and the inner leaflet a mixture of stearoyl-oleoyl-phosphatidylserine (SOPS) with cholesterol. For comparison purposes, we also performed two simulations on symmetric bilayers: the first simulation was performed on a bilayer containing a binary mixture of SOPS with cholesterol; the second contained a mixture of SM with cholesterol. We studied the hydrogen-bonding network of the bilayers in our simulations and the difference in the network properties in the monolayers either with SM or SOPS. We observed that in the asymmetric bilayer the properties of monolayers were the same as in the corresponding monolayers in the symmetric bilayers.
Cholesterol↗
High sensitivity of PHHC rat to dietary cholesterol.
The Prague Hereditary Hypercholesterolaemic (PHHC) rat is a strain of the Wistar rat very sensitive to dietary cholesterol. The dynamics of changes in serum and liver lipids and lecithin: cholesterol acyltransferase (LCAT) were studied immediately after the switch to a high cholesterol diet. Immediate cumulation of free and esterified cholesterol in the liver after the increase in alimentary cholesterol intake is supposed to be the regulating step leading to a subsequent increase in serum cholesterol concentration. Activity of LCAT was negatively correlated to the concentration of free cholesterol in the liver, very early after the cholesterol diet was introduced, a possibility of a down regulation of enzyme synthesis similarly to the regulation of synthesis of cholesterol in hepatocytes was observed.
Animals↗
An overview of reverse cholesterol transport.
Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma compartment. Cellular cholesterol efflux is mediated by HDL, acting in conjunction with the cholesterol esterifying enzyme, lecithin: cholesterol acyltransferase. Cholesteryl ester accumulating in HDL can then follow a number of different fates: uptake in the liver in HDL containing apolipoprotein (particle uptake) by LDL receptors, selective uptake of HDL cholesteryl ester in liver or other tissues involving scavenger receptor B1, or transfer to triglyceride-rich lipoproteins as a result of the activity of cholesteryl ester transfer protein, with subsequent uptake of triglyceride-rich lipoprotein remnants in the liver. Recently, we and others have taken a molecular approach to analysing the different components of reverse cholesterol transport, by over- or under-expression of individual molecules in induced mutant mouse models, or by the study of human mutations involving molecules of reverse cholesterol transport. Such studies reveal that over-expression of the major HDL apoprotein, apolipoprotein A-I, is clearly anti-atherogenic. However, over- or under-expression of molecules such as cholesteryl ester transfer protein, which have opposite effects on HDL levels and reverse cholesterol transport, suggest that both HDL levels as well as the dynamics of cholesterol movement through HDL are involved in the anti-atherogenic actions of HDL.
Animals↗
Cholesterol turnover and risk factors for the development of coronary heart disease.
Lecithin cholesterol acyltransferase (LCAT) appears to be one of the factors controlling the intravascular turnover rate of cholesterol. LCAT activity in healthy subjects is significantly higher in men than in women of the same relative body weight, total and free cholesterol and triglycerides. In healthy men sleep deprivation induced a decrease in LCAT activity combined with a decline of serum cholesterol concentration; consequently, the intravascular turnover rate of cholesterol did not significantly change. In hypertensive patients the decrease in cholesterol turnover rate correlated with the degree of hypertension and the response of blood pressure to medication. Reduced turnover rate of cholesterol was more frequent in men than in women, in spite of higher plasma cholesterol concentration in the latter. During a 4-month period of treatment etiroxate of hyperlipoproteinemia II and IV, the only significant change in plasma cholesterol level was a drop observed after the first two weeks; on the other hand, the turnover rate of cholesterol rose gradually and approached normal values due to a highly increased LCAT activity. Obesity and diabetes were associated with a high percentage of deviations in the studied parameters of cholesterol metabolism. The turnover rate of cholesterol measured three months after acute myocardial infarction was below normal in 80% of patients, whereas hypercholesterolemia was manifested in only less than 40%. The results imply that the intravascular turnover rate of cholesterol estimated by measurement of LCAT activity may be a suitable indicator of the internal balance of cholesterol, substantially more delicate and discriminative than a mere determination of the actual plasma concentration of cholesterol or plasma lipoprotein. Judging by our observations, deviations in the internal dynamics of cholesterol may play an important role in the pathogenesis of coronary atherosclerosis.
Cholesterol↗
Physical effects of biologically formed cholesterol oxidation products on lipid membranes investigated with fluorescence depolarization spectroscopy and electron spin resonance.
Planar oriented membranes of 1-palmitoyl, 2-oleoyl-phosphatidylcholine (POPC) containing cholesterol, 19-hydroxycholesterol, 22S-hydroxycholesterol, or 25-hydroxycholesterol in concentrations up to 5 mol % were investigated with angle-resolved fluorescence depolarization and electron spin resonance measurements. Analyses of the data with the Brownian diffusion model show that the oxysterols have structural effects similar to those of cholesterol: an increase in molecular order and no change in the rotational diffusion coefficients of the probe molecules. Time-resolved fluorescence anisotropy measurements on diphenylhexatriene (DPH) in small unilamellar vesicles of POPC and DOPC were performed using oxysterols commonly found in oxidized low density lipoproteins (LDL) in comparison to membranes containing cholesterol or no sterols. Analyses using the Brownian rotational diffusion model show that most LDL-oxysterols affect the vesicle physical structure in a manner similar to cholesterol, viz. an increase in molecular order and a decrease in the dynamics. Cholesterol-alpha-epoxide has a much smaller ordering effect than cholesterol in POPC-vesicles. A similar effect was found for 7 beta-hydroxycholesterol in DOPC-vesicles. The tendency of the oxysterols to influence the molecular order as compared to pure cholesterol may contribute to cell membrane permeability changes affecting crucial cell functions and events leading to vascular cell injury. Increased LDL oxysterol levels may account for some of the structural changes noted for oxidatively modified LDL as well as its toxicity to vascular cells.
Cholesterol↗
Diet-induced hyperlipidemia in cattle modifies the intrafollicular cholesterol environment, modulates ovarian follicular dynamics, and hastens the onset of postpartum luteal activity.
Three experiments were conducted with female cattle during the postpartum period and during the estrous cycle to examine the effects of diet-induced hyperlipidemia on lipoprotein-cholesterol and triglyceride (TG) metabolism, ovarian follicular dynamics, and incidence of postpartum luteal activity. Dietary-lipid effects were examined independently of metabolizable energy intake. Feeding a high-lipid (HL) diet (8% total lipid) for the first 3 wk of the puerperium (Experiment 1) increased (p less than 0.0001) the concentration of total cholesterol and high-density lipoprotein-cholesterol (HDL-CH), but not TG, within follicular fluid (FF) of estrogen-active (E-A) and inactive (E-I) follicles. Increases (1.4- to 1.7-fold) were similar in proportion to those observed in peripheral blood serum, but absolute concentrations were about 45% of that in serum. Greater than 95% of the cholesterol in FF was HDL-CH, with a greater (p less than 0.06) proportion of HDL-CH sequestered by E-A compared to E-I follicles. The HL diet increased (p less than 0.06) the number of medium-sized (3.1-9.9 mm) follicles present at ovariectomy 19-21 days postcalving and increased (p less than 0.03) concentrations of FF androstenedione in E-I follicles 5-fold. Granulosa cells from preovulatory follicles (Experiment 2) of heifers fed HL diets secreted 2.1- to 3.5-fold greater (p less than 0.03) quantities of pregnenolone and progesterone in vitro. Finally, feeding HL supplements to postpartum range cattle for 30 days increased (p less than 0.05) the incidence of ovarian luteal activity by 18% (Experiment 3). Shifts in lipid metabolic status modify reproductive potential in cattle, independently of dietary energy intake.
Androstenedione↗
Origin and fate of cholesterol in rat plasma lipoproteins in vivo. II. Modelling of cholesterol absorption and its release into plasma lipoproteins.
After a single ingestion of a diet containing 14C-cholesterol, cholesterol radioactivity in the stomachal and intestinal contents, in the different organs and in the very low density lipoproteins (VLDL) and chylomicrons was measured at different times during 2 days. Based on the results, a quantitative model of cholesterol absorption and of its release into the VLDL and chylomicrons has been elaborated. This model takes into account the different processes implied in the turnover of intestinal cholesterol and that of the entire organism. It constitutes a coherent whole (satisfactory simulations for the variables studied, suitable mass balances for each compartment and the absence of major contradictions with preexisting quantitative data). Once again the model demonstrates the important part played by the intestine in rat cholesterol system dynamics. It takes into account the existence of two related exogenous and endogenous cholesterol pools from which the cholesterol released by the intestine into the chylomicrons and VLDL originates. The results suggest the existence of an important esterified cholesterol uptake from other plasma lipoproteins by the chylomicrons.
Animals↗
Molecular dynamics simulations of phospholipid bilayers with cholesterol.
To investigate the microscopic interactions between cholesterol and lipids in biological membranes, we have performed a series of molecular dynamics simulations of large membranes with different levels of cholesterol content. The simulations extend to 10 ns, and were performed with hydrated dipalmitoylphosphatidylcholine (DPPC) bilayers. The bilayers contain 1024 lipids of which 0-40% were cholesterol and the rest DPPC. The effects of cholesterol on the structure and mesoscopic dynamics of the bilayer were monitored as a function of cholesterol concentration. The main effects observed are a significant ordering of the DPPC chains (as monitored by NMR type order parameters), a reduced fraction of gauche bonds, a reduced surface area per lipid, less undulations--corresponding to an increased bending modulus for the membrane, smaller area fluctuations, and a reduced lateral diffusion of DPPC-lipids as well as cholesterols.
1,2-Dipalmitoylphosphatidylcholine↗
Characterization of cholesterol-sphingomyelin domains and their dynamics in bilayer membranes.
Lipids segregate with each other into small domains in biological membranes, which can facilitate the associations of particular proteins. The segregation of cholesterol and sphingomyelin (SPM) into domains known as rafts is thought to be especially important. The formation of rafts was studied by using planar bilayer membranes that contained rhodamine-phosphatidylethanolamine (rho-DOPE) as a fluorescent probe, and wide-field fluorescence microscopy was used to detect phase separation of the probe. A fluorescently labeled GM(1), known to preferentially partition into rafts, verified that rho-DOPE faithfully reported the rafts. SPM-cholesterol domains did not form at high temperatures but spontaneously formed when temperature was lowered to below the melting temperature of the SPM. Saturated acyl chains on SPMs therefore promote the formation of rafts. The domains were circular (resolution > or = 0.5 microm), quickly reassumed their circular shape after they were deformed, and merged with each other to create larger domains, all phenomena consistent with liquid-ordered (l(o)) rather than solid-ordered (s(o)) domains. A saturated phosphatidylcholine (PC), disteoryl-PC, could substitute for SPM to complex with cholesterol into a l(o)-domain. But in the presence of cholesterol, a saturated phosphatidylethanolamine or phosphatidylserine yielded s(o)-domains of irregular shape. Lipids with saturated acyl chains can therefore pack well among each other and with cholesterol to form l(o)-domains, but domain formation is dependent on the polar headgroup of the lipid. An individual raft always extended through both monolayers. Degrading cholesterol in one monolayer with cholesterol oxidase first caused the boundary of the raft to become irregular; then the raft gradually disappeared. The fluid nature of rafts, demonstrated in this study, may be important for permitting dynamic interactions between proteins localized within rafts.
Acylation↗
Solid-state 2H NMR studies of the effects of cholesterol on the acyl chain dynamics of magnetically aligned phospholipid bilayers.
We report the utilization of magnetically aligned phospholipid bilayers (bicelles) to study the effects of cholesterol in phospholipid bilayers for both chain perdeuterated DMPC and partially deuterated alpha-[2,2,3,4,4,6-d(6)]-cholesterol using (2)H solid-state NMR spectroscopy. The quadrupolar splittings at 40 degrees C were 25.5 and 37.7 kHz, respectively, for the 2,4-(2)H(eq) and 2,4-(2)H(ax) deuterons when the bilayer normal of the discs was aligned perpendicular to the static magnetic field. The quadrupolar splittings were doubled when Yb(3+) ions were added to flip the bicelles 90 degrees such that the bilayer normal was colinear with the magnetic field. The results suggest that cholesterol is incorporated into the bicelle discs. For chain perdeuterated DMPC-d(54), incorporated into DMPC-DHPC bicelle discs, the individual quadrupolar splittings of the methylene and methyl groups doubled on going from the perpendicular to the parallel alignment. Also, the presence of cholesterol increased the overall ordering of the acyl chains of the phospholipids. S(CD) (i) calculations were extracted directly from the (2)H quadrupolar splittings of the chain perdeuterated DMPC. The order parameter, S(CD) (i), calculations clearly indicated an overall degree of ordering of the acyl chains in the presence of cholesterol. We also noted a disordering effect at higher temperatures. This study demonstrates the ease with which (2)H order parameters can be calculated utilizing magnetically aligned phospholipid bilayers when compared with randomly dispersed membrane samples.
Cholesterol↗
Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.
Plasma high density lipoprotein (HDL) levels are strongly genetically determined and show a general inverse relationship with coronary heart disease (CHD). The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key participant in the reverse transport of cholesterol from the periphery to the liver. A high prevalence of two different CETP gene mutations (D442G, 5.1%; intron 14G:A, 0.5%), was found in 3,469 men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL chol levels (+10% for D442G). However, the overall prevalence of definite CHD was 21% in men with mutations and 16% in men without mutations. The relative risk (RR) of CHD was 1.43 in men with mutations (P < .05); after adjustment for CHD risk factors, the RR was 1.55 (P = .02); after additional adjustment for HDL levels, the RR was 1.68 (P = .008). Similar RR values were obtained for the D442G mutation alone. Increased CHD in men with mutations was primarily observed for HDL chol 41-60 mg/dl; for HDL chol > 60 mg/dl men with and without mutations had low CHD prevalence. Thus, genetic CETP deficiency appears to be an independent risk factor for CHD, primarily due to increased CHD prevalence in men with the D442G mutation and HDL cholesterol between 41 and 60 mg/dl. The findings suggest that both HDL concentration and the dynamics of cholesterol transport through HDL (i.e., reverse cholesterol transport) determine the anti-atherogenicity of the HDL fraction.
Aged↗
Rod-like cholesterol micelles in aqueous solution studied using polarized and depolarized dynamic light scattering.
Micelles of cholesterol in aqueous solution have been investigated using polarized and depolarized dynamic light scattering. They are shown to be highly extended and characterized by a narrow size distribution. It is shown that a rod-like model is applicable with length, L = 580 nm. Determination of the rotational diffusion coefficient by analysis of the autocorrelation function gave a value of theta = 150 s-1, which is close to the calculated value for the rod with this dimension. Depolarized dynamic light scattering measurements as a function of angle gave a value of 110 s-1.
Biophysical Phenomena↗
Lipid lateral diffusion in bilayers with phosphatidylcholine, sphingomyelin and cholesterol. An NMR study of dynamics and lateral phase separation.
Pulsed field gradient (pfg)-NMR measurements of the lipid lateral diffusion coefficients in several macroscopically aligned bilayer systems were summarized from previous and new studies. The aim was to carry out a comparison of the translational dynamics for bilayers with various mixtures of l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and chicken egg yolk sphingomyelin (eSM), with or without cholesterol. New useful information was obtained on the dynamics in these lipid bilayers that has not been previously appreciated. Thus, we were able to propose that the driving force behind the phase separation into l(d)and l(o)phases evolves from the increasing difficulty to incorpotate DOPC into a highly ordered phase. Our results suggest that DOPC has a preference to be located in a disordered phase, while DPPC and eSM prefer the ordered phase. Quite unexpectedly, CHOL seems to partition into both phases to roughly the same extent, indicating that CHOL has no particular preference for any of the l(d)or l(o) phases, and there are no specific interactions between CHOL and saturated lipids.
1,2-Dipalmitoylphosphatidylcholine↗
[Action of cytoplasmic factors from the regenerating liver on cholesterol esterification in the blood serum of rats with tetrachloromethane liver damage].
The effect of proliferation stimulating factors (PSF) obtained from regenerating liver on the cholesterol esterification in blood serum under deep tetrachloromethane intoxication has been studied in experiments with white rats. Three phases in dynamics of cholesterol content in blood serum have been picked out after a single tetrachloromethane injection. The content of total cholesterol and cholesterol esters reduces during the first phase (24 h), during the second phase (3-7th day) it increases and during the third phase (15th day) these values become normal. PSF injection does not produce any influence on the nature of blood cholesterol under deep tetrachloromethane intoxication, but stimulates the processes of cholesterol ester formation in blood serum.
Animals↗
[Age and characteristics of cholesterol biosynthesis in rat liver under normal conditions and during atherogenic loading].
Intraperitoneal injection of C14CH3COONa to normal rats aged 6--8 and 28--32 months revealed a slower dynamics of cholesterol biosynthesis in the liver of old rats at the maximum of the tracer incorporation was lower than in the young ones. Atherogenic diet (0.25 g of cholesterol per 100 g of animal weight for a period of 20 days) was accompanied by an increase in the total cholesterol content and depressio of its biosynthesis in the liver, more pronounced in the young rats. Continued cholesterol administration caused further depression of its biosynthesis, most pronounced (in this case) in the old animals.
Acetates↗