Cholesterol Journal Articles

Record 3121 to 3140

Cholesterol-fed rabbits: study of the response of the vas deferens to adrenergic and non-adrenergic stimulus and to a kappa-opioid agonist
Alfaro, M. J., M. J. Ormazabal, et al. (1996), J Pharm Pharmacol 48(4): 433-6.
Abstract: The aim of the present study was to analyse the contractility of the isolated vas deferens from hypercholesterolaemic rabbits; for this purpose we evaluated the contractile response induced by noradrenaline and by electrical stimulation. A significant increase in the amplitude of adrenergic and non-adrenergic responses was observed in vas deferens from hypercholesterolaemic rabbits. These data suggest an increase in the contractility of the smooth muscle in these animals.

Cholesterol-free diet with a high ratio of polyunsaturated to saturated fatty acids in heterozygous familial hypercholesterolemia: significant lowering effect on plasma cholesterol
Mokuno, H., N. Yamada, et al. (1990), Horm Metab Res 22(4): 246-51.
Abstract: We have studied the effect of diet therapy on plasma lipoprotein metabolism in heterozygous familial hypercholesterolemia. Seven patients with a mean plasma cholesterol concentration of 323 +/- 67 mg/dl were hospitalized and kept on a cholesterol-free diet for as long as 11 days without any medication. The content of dietary cholesterol was approximately 1.4 mg a day, and dietary fat, carbohydrate and protein comprised 18.0, 69.2 and 12.8% of calories, respectively. The ratio of polyunsaturated to saturated fatty acids (P/S) was 3.1. At the end of the study period, plasma cholesterol was lowered by 14.2%, from 323 to 277 mg/dl, and low density lipoprotein (LDL) cholesterol by 17.5% from 229 to 189 mg/dl. Using density gradient ultracentrifugation, the major change in LDL cholesterol was found to be in those fractions with a mean density between 1.034 and 1.042, where cholesterol concentrations decreased from 132 to 87 mg/dl (34%). These results indicate that diet therapy with free-cholesterol and a high ratio of P/S is highly effective in controlling plasma cholesterol levels in heterozygous familial hypercholesterolemia.

Cholesterol-free foods: where's the trans?
Holub, B. J. (1991), Cmaj 144(3): 330.

Cholesterol-gallstone formation: more than a biliary lipid defect?
van Erpecum, K. J. (2004), J Lab Clin Med 144(3): 121-3.

Cholesterol--how much do we disagree?
Angelin, B. (1992), Lakartidningen 89(41): 3389-90.

Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia
Miida, T., S. Hirayama, et al. (2004), J Atheroscler Thromb 11(5): 253-64.
Abstract: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. Statins inhibit cholesterol biosynthesis, leading to enhanced uptake of low-density lipoprotein (LDL) from the circulation via LDL receptors. This strong cholesterol-lowering action contributes to the beneficial effects of statins. For example, large clinical trials have demonstrated that statins significantly reduce cardiovascular risk. Recent research has shown that statins have other multiple actions involved in endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" of statins probably provide a significant contribution to the reduction of cardiovascular events. This review summarizes the pleiotropic actions of statins in both basic and clinical studies. It also considers the potential for statin therapy in the treatment of stroke and dementia.

Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat
Gerber, R. T., K. Holemans, et al. (1999), J Physiol 517 (Pt 2): 607-16.
Abstract: 1. Western diets high in saturated fat are associated with an increased incidence of cardiovascular diseases. In this study we have evaluated vascular endothelial function and oxidative stress in virgin rats fed a normal (VC) or high in saturated fat diet (VHF) (20 % lard and corn oil w/w) from weaning until adulthood, and throughout subsequent pregnancy (PC and PHF, respectively). 2. The saturated fat diet was associated with enhanced noradrenaline sensitivity in small mesenteric arteries from VHF rats (VHF vs. VC, P < 0.05) and blunted endothelium-dependent relaxation in VHF and PHF rats (VHF vs. VC, P < 0.001; PHF vs. PC, P < 0.05). Endothelial dysfunction was attributable to a reduced nitric oxide component of relaxation in VHF rats, and blunted prostacyclin and endothelium-derived hyperpolarizing factor components in PHF rats. 3. Other than plasma cholesterol, which was reduced in VHF and PHF rats, plasma lipids were normal. Fasting plasma insulin and glucose concentrations were raised in VHF rats (P < 0.05) and the plasma marker of oxidative stress, 8-iso PGF2alpha, was increased in PHF animals (P < 0.01). 4. These findings suggest that endothelial dysfunction induced by a saturated fat diet is cholesterol independent and likely to be of different mechanistic origin in virgin and pregnant rats.

Cholesterol-independent interactions with CD47 enhance alphavbeta3 avidity
McDonald, J. F., A. Zheleznyak, et al. (2004), J Biol Chem 279(17): 17301-11.
Abstract: Expression in OV10 cells of either wild-type CD47 or its extracellular IgV domain linked to a glycosylphosphatidylinositol anchor-(IgV-GPI) enhanced ligand-induced alpha(v)beta(3) activation as detected by the binding of LIBS1 and LIBS6 mAbs. The amplitude of LIBS binding was greater with both CD47 and IgV-GPI expression, indicating an increase in the population of "activable" integrin molecules. Expression of either CD47 species also increased alpha(v)beta(3)-mediated adhesion to vitronectin, and to surfaces coated with the anti-beta(3) antibody AP3, because of enhanced clustering of alpha(v)beta(3) as confirmed by chemical cross-linking. Cholesterol depletion with methyl-beta-cyclodextrin did not prevent the increase in anti-LIBS binding, but reduced cell adhesion to vitronectin and AP3. However, cells expressing CD47 were partially insulated against this disruption, and IgV-GPI was even more effective. Both CD47 and IgV-GPI were found in cholesterol-rich rafts prepared in the absence of detergent, but only CD47 could recruit alpha(v)beta(3) and its associated signaling molecules to these domains. Thus CD47-alpha(v)beta(3) complexes in cholesterol-rich raft domains appear to engage in G(i)-dependent signaling whereas CD47-alpha(v)beta(3) interactions that lead to integrin clustering are also detergent resistant, but are insensitive to cholesterol depletion and do not require the transmembrane region of CD47.

Cholesterol-independent membrane disruption caused by triterpenoid saponins
Hu, M., K. Konoki, et al. (1996), Biochim Biophys Acta 1299(2): 252-8.
Abstract: The membrane-disrupting activity of 15 triterpenoid saponins, obtained from Chinese plants of the genus Aralia, was investigated using phosphatidylcholine liposomes with and without cholesterol. The permeability of the membrane was examined by monitoring the induced fluorescent dye release from the liposome. On the basis of the obtained results, the structure-activity relationship among glucuronides of oleanolic acid was discussed. This takes into account particularly the variation in the carboxyl function. Namely, the saponins could induce a permeability change on liposomal membrane without cholesterol when they are glycosylated at both C-3 and C-28 of the oleanolic acid. There also exists a great similarity in the time-course curves for dye-release within such saponins, reflecting their similar action with the lipid bilayer membrane. The saponins glycosylated only at C-3 could also exhibit the same activity with somewhat different action profiles when the glucuronic acid is esterified, while those with the free glucuronic acid required cholesterol in the liposomes to induce permeability change thereof.

Cholesterol-independent targeting of Golgi membrane proteins in insect cells
Rolls, M. M., M. T. Marquardt, et al. (1997), Mol Biol Cell 8(11): 2111-8.
Abstract: Distinct lipid compositions of intracellular organelles could provide a physical basis for targeting of membrane proteins, particularly where transmembrane domains have been shown to play a role. We tested the possibility that cholesterol is required for targeting of membrane proteins to the Golgi complex. We used insect cells for our studies because they are cholesterol auxotrophs and can be depleted of cholesterol by growth in delipidated serum. We found that two well-characterized mammalian Golgi proteins were targeted to the Golgi region of Aedes albopictus cells, both in the presence and absence of cellular cholesterol. Our results imply that a cholesterol gradient through the secretory pathway is not required for membrane protein targeting to the Golgi complex, at least in insect cells.

Cholesterol-induced alteration of apolipoprotein A-I conformation in reassembled high density lipoprotein
Talussot, C. and G. Ponsin (1991), Biochimie 73(9): 1173-8.
Abstract: Recent reports have shown that apolipoprotein A-I (apo A-I), the major protein of high density lipoprotein (HDL) may exist in different conformational states. We studied the effects of apolipoprotein A-II and/or cholesterol on the conformation of apo A-I in reassembled HDL. Analysis of tryptophan fluorescence quenching in the presence of iodine suggested that cholesterol increased the number of apo A-I tryptophan residues accessible to the aqueous phase, but decreased their mean degree of hydration. These observations cannot be totally explained on the basis of the effect of cholesterol on phospholipid viscosity as determined by fluorescence anisotropy of diphenyl hexatriene. We did not observe any effect of apo A-II on the conformation of apo A-I.

Cholesterol-induced alterations of the packing properties of gangliosides: an EPR study
Pincelli, M. M., P. R. Levstein, et al. (2000), Chem Phys Lipids 104(2): 193-206.
Abstract: The effect of cholesterol (Chol) on two kinds of glycolipid assemblies, one composed of monosialogangliosides (GM1a) and the other formed by a natural mixture of bovine brain gangliosides (TBG), has been analysed. The experimental approach involves spin label electron paramagnetic resonance (EPR) in aqueous lipid dispersions. The employment of a hydrosoluble spin label and a 'quencher' of the EPR signal that is not able to permeate lipid interfaces, allowed us to conclude that GM1a/Chol mixtures give rise to vesicles at Chol proportions for which TBG/Chol mixtures form micelles. The use of different liposoluble spin labels reveals that cholesterol produces a straightening of the hydrocarbon chains in both lipid systems. In GM1a/Chol mixtures, this feature is more pronounced and it is coupled with a decrease in polarity at the chain ends.

Cholesterol-induced changes of type VIII collagen expression and distribution in carotid arteries of rabbit
Plenz, G., A. Dorszewski, et al. (1999), Arterioscler Thromb Vasc Biol 19(10): 2395-404.
Abstract: Lipoproteins play a major role in cardiovascular disease and atherosclerosis. In the vascular wall, they strongly influence the organization of extracellular matrix. The present study set out to investigate the changes in the extracellular matrix of the vessel wall induced by atherogenic diet, focusing on type VIII collagen, a vascular collagen that has not previously been investigated in detail. The influence of cholesterol diet on the expression, distribution, and deposition of type VIII collagen was examined in carotid arteries of New Zealand White rabbits. Carotid arteries of rabbits receiving diet supplemented with 1% cholesterol for 6 weeks and those on the same regimen followed by normal chow for 1 day, 10 days, 5 weeks, and 12 weeks were studied and compared with controls not exposed to the cholesterol diet. Carotid arteries of normocholesterolemic rabbits contained type VIII collagen-expressing cells in all layers, with focal accumulations of expressing cells in the subendothelial areas, the outer medial zone, and the adventitia. In response to cholesterol diet, type VIII collagen synthesis was reduced in media and adventitia and the distribution patterns changed. Expressing cells were found predominantly in the endothelium, and type VIII collagen accumulated in the intimal space. Immunogold labeling for electron microscopy revealed that type VIII collagen in the intima is associated with microfibrils extending from the internal elastic lamina. Withdrawal of cholesterol resulted in reestablishment of the normal distribution pattern. Northern and Western blot analyses supported the immunoconfocal and in situ hybridization data, demonstrating decreased type VIII collagen expression in response to cholesterol diet and progressive recovery to normal levels with time after withdrawal of cholesterol. Our study demonstrates that type VIII collagen is modulated in the presence of cholesterol. The data indicate that type VIII collagen is specifically remodeled during early experimental atherosclerosis, implying a role for this extracellular matrix component in neointimal growth.

Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles
Adams, C. M., J. L. Goldstein, et al. (2003), Proc Natl Acad Sci U S A 100(19): 10647-52.
Abstract: Sterols mediate feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway by preventing movement of the SREBP cleavage-activating protein (SCAP)/SREBP complex from endoplasmic reticulum (ER) to Golgi, where proteolytic cleavage of SREBPs releases the transcription factor domain that activates genes for lipid biosynthesis. Our laboratory previously used a trypsin cleavage assay to show that the conformation of SCAP is altered in vitro by addition of cholesterol to ER membranes. More recently, Insig-1 and Insig-2 were identified as ER resident proteins that bind the SCAP/SREBP complex and promote its ER retention when cells are treated with sterols. Here, we use the trypsin assay to show that Insig proteins reduce the concentration of cholesterol needed in vitro to produce the conformational change in SCAP. Insig-1 and Insig-2 also enhance the conformational change in SCAP that occurs upon addition of certain cationic amphiphiles, such as chlorpromazine, trifluoperazine, and imipramine, which mimic the effect of cholesterol. The effects of cationic amphiphiles raise the possibility that SCAP may monitor specifically the composition of the cytoplasmic leaflet of the ER membrane.

Cholesterol-induced fluid-phase immiscibility in membranes
Sankaram, M. B. and T. E. Thompson (1991), Proc Natl Acad Sci U S A 88(19): 8686-90.
Abstract: The fluid-phase behavior of binary mixtures of cholesterol with phosphatidylcholines is investigated using magnetic resonance methods. Phospholipid biradicals provide the electron spin resonance spectroscopic resolution of two immiscible fluid phases in the dipalmitoylphosphatidylcholine-cholesterol system. Isotropic chemical shifts of the phospholipid carbonyl carbons in binary mixtures with cholesterol measured using solid-state high-resolution nuclear magnetic resonance methods furnish evidence for a putative hydrogen bond between the 3 beta-hydroxyl of cholesterol and the sn-2 carbonyl of the phospholipid. The location in the bilayer of cholesterol in the two fluid phases is determined by measuring spin label-enhanced spin-lattice relaxation rates of the 13C nuclei of both the phospholipid and cholesterol molecules. These results suggest, in a time-averaged sense, that in the cholesterol-poor fluid phase the cholesterol molecule essentially spans the bilayer, whereas in the cholesterol-rich fluid phase the molecule is present in both monolayers of the bilayer.

Cholesterol-induced growth stimulation, macromolecule synthesis, and increased phosphoinositide metabolism of ascites tumour cells in culture
Haeffner, E. W. and U. Wittmann (1999), Cell Signal 11(11): 821-9.
Abstract: Ascites tumour cells have previously been shown by us to require exogenous cholesterol for growth. To investigate further this phenomenon, we have used, in addition to free cholesterol, cholesterol complexed to digitonine, to elaborate the specificity of this growth-controlling process using a chemically defined medium. Our data show that only free cholesterol stimulates cell growth and macromolecule synthesis in a dose-dependent manner, suggesting that the proper embedding of the sterol into the membrane is a prerequisite for its function. Furthermore, studies have been performed on the influence of cholesterol on the phosphoinositide metabolism of our cells, as phosphoinositides furnish important second messenger molecules in the cascade of signal transduction. We could show that cholesterol stimulates a transient release of inositol trisphosphate and other inositol phosphates by inducing the activation of phospholipase C (PLC). PLC activation by a factor of about 3 with phosphatidylinositol 4-phosphate and phosphatidyl inositol 4,5-bisphosphate as substrates could be measured directly by using a partially purified membrane preparation. This enzyme activity was found to be strongly dependent on free Ca2+ ions with optimal concentrations of 100 nM for cholesterol- and 50 nM for cholesterol-digitonide-treated cells. Ca2+ concentration for half-maximum activation, however, was identical under both conditions. Phospholipase C activity could be synergistically increased about 2-fold with 25 microg GTP gammaS in cholesterol-digitonide-treated cells as well, suggesting that the coupling between phospholipase C and the G-protein was not disturbed by the complex. These data demonstrate a functional role of cholesterol on cell growth, macromolecule synthesis, and phosphoinositide metabolism mediating the release of important second messenger molecules.

Cholesterol-induced interfacial area condensations of galactosylceramides and sphingomyelins with identical acyl chains
Smaby, J. M., M. Momsen, et al. (1996), Biochemistry 35(18): 5696-704.
Abstract: The interfacial interactions occurring between cholesterol and either galactosylceramides (GalCers) or sphingomyelins (SMs) with identical acyl chains have been investigated using Langmuir film balance techniques. Included among the synthesized GalCers and SMs were species containing palmitoyl (16:0), stearoyl (18:0), oleoyl 18:1 delta 9(c), nervonoyl 24:1 delta 15(c), or linoleoyl 18:2 delta 9,12(c) acyl residues. The cholesterol-induced condensations in the average molecular areas of the monolayers were determined by classic mean molecular area vs composition plots as well as by expressing the changes in terms of sphingolipid cross-sectional area reduction over the surface pressure range from 1 to 40 mN/m (at 1 mN/m intervals). The results show that, at surface pressures approximating bilayer conditions (30 mN/m), acyl heterogeneity in naturally occurring SMs (bovine of egg SM) enhanced the area condensation induced by cholesterol compared with their predominant molecular species (e.g. 18:0 SM in bovine SM; 16:0 SM in egg SM). Nonetheless, cholesterol always had a greater condensing effect on SM compared to GalCer when these sphingolipids were acyl chain matched and in similar phase states (prior to mixing with cholesterol). Also, the cholesterol-induced area changes for a given sphingolipid type (e.g. SM or GalCer) were similar whether the acyl chains were saturated, cis-delta 9-monounsaturated, or cis-delta 9,12-diunsaturated if the sphingolipids were in similar phase states (prior to mixing with cholesterol) and compared at equivalent surface pressures. These results indicate that, under conditions were hydrocarbon structure is matched, the sphingolipid head group plays a dominant role in determining the extent to which cholesterol reduces sphingolipid cross-sectional area. Despite the larger cholesterol-induced area condensations observed in SMs compared to those in GalCers, the molecular-packing densities showed that equimolar GalCer-cholesterol films were generally packed as tight as or slightly tighter than those of the SM-cholesterol films. The results are discussed in terms of a molecular model for sphingolipid-cholesterol interactions. Our findings also do only raise questions as to whether cholesterol-induced condensation data provide a reliable measure of the affinity, i.e. interaction strength, between cholesterol and different lipids but also provide insight regarding the stability of sterol/sphingolipid 1-1 rich microdomains thought to exist in caveolae and other cell membrane regions.

Cholesterol-induced modifications in lipid bilayers: a simulation study
Chiu, S. W., E. Jakobsson, et al. (2002), Biophys J 83(4): 1842-53.
Abstract: 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.

Cholesterol-induced modulated phase in phospholipid membranes
Karmakar, S. and V. A. Raghunathan (2003), Phys Rev Lett 91(9): 098102.
Abstract: We report the observation of a cholesterol-induced modulated phase (Pbeta) in dipalmitoyl phosphatidylcholine bilayers. It occurs below the main transition of the lipid at cholesterol concentrations of around 15 to 20 mol % and is distinct from the ripple (Pbeta') phase found in between the main and pretransitions at lower cholesterol concentrations. An electron density map of this phase, constructed from x-ray diffraction data from oriented multilayers, shows that the bilayers in this phase have a one-dimensional periodic height modulation with an amplitude of about 2.5 A. A partial phase diagram of the system deduced from diffraction data is in broad agreement with earlier studies.

Cholesterol-induced protein sorting: an analysis of energetic feasibility
Lundbaek, J. A., O. S. Andersen, et al. (2003), Biophys J 84(3): 2080-9.
Abstract: The mechanism(s) underlying the sorting of integral membrane proteins between the Golgi complex and the plasma membrane remain uncertain because no specific Golgi retention signal has been found. Moreover one can alter a protein's eventual localization simply by altering the length of its transmembrane domain (TMD). M. S. Bretscher and S. Munro (SCIENCE: 261:1280-1281, 1993) therefore proposed a physical sorting mechanism based on the hydrophobic match between the proteins' TMD and the bilayer thickness, in which cholesterol would regulate protein sorting by increasing the lipid bilayer thickness. In this model, Golgi proteins with short TMDs would be excluded from cholesterol-enriched domains (lipid rafts) that are incorporated into transport vesicles destined for the plasma membrane. Although attractive, this model remains unproven. We therefore evaluated the energetic feasibility of a cholesterol-dependent sorting process using the theory of elastic liquid crystal deformations. We show that the distribution of proteins between cholesterol-enriched and cholesterol-poor bilayer domains can be regulated by cholesterol-induced changes in the bilayer physical properties. Changes in bilayer thickness per se, however, have only a modest effect on sorting; the major effect arises because cholesterol changes also the bilayer material properties, which augments the energetic penalty for incorporating short TMDs into cholesterol-enriched domains. We conclude that cholesterol-induced changes in the bilayer physical properties allow for effective and accurate sorting which will be important generally for protein partitioning between different membrane domains.

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