| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol: the alarm and fear Broomes, E. L. (1990), J Natl Med Assoc 82(4): 237, 256, 264. |
| Cholesterol:phospholipid ratio is elevated in platelet plasma membrane in patients with hypertension Benjamin, N., B. F. Robinson, et al. (1990), J Hum Hypertens 4(3): 273-6. Abstract: The cholesterol:phospholipid ratio was measured in platelet plasma membrane, red blood cell (RBC) membranes, low density lipoprotein (LDL) and whole plasma in patients with primary hypertension and in matched normal controls. The cholesterol:phospholipid ratio was raised in the platelet membrane from hypertensive patients compared with that from normal controls (0.65 +/- 0.03 vs 0.53 +/- 0.02: mean +/- SEM; P less than 0.01). The ratio observed in RBC membranes, LDL and whole blood was similar in the two groups. If this abnormality in the lipid composition of platelet plasma membrane is present in other cells it could account for some of the changes in cell membrane function that have been described in hypertension. |
| Cholesterol-3-beta, 5-alpha, 6-beta-triol induced genotoxicity through reactive oxygen species formation Cheng, Y. W., J. J. Kang, et al. (2005), Food Chem Toxicol 43(4): 617-22. Abstract: The mutagenicity of oxysterols, cholesterol-3beta,5alpha,6beta-triol (alpha-Triol), 7-keto-cholesterol (7-Keto) and cholesterol-5alpha,6alpha-epoxide (alpha-Epox) were examined by the Ames method and chromosome aberration test in this study. Only alpha-Triol concentration-dependently caused an increase of bacterial revertants in the absence of metabolic activating enzymes (S9), but not 7-keto and alpha-Epox. The mutagenic effect of alpha-Triol was reduced by the addition of S9. On the other hand, although alpha-Triol significantly induced chromosome aberration in CHO-K1 cells with and without S9. However, the addition of S9 reduced the degree of abnormal structure chromosome compared to without S9 mix. Catalase and superoxide dismutase (SOD) inhibited alpha-Triol induced increase of revertants in Salmonella typhimurium and chromosome aberration frequency in CHO cells, suggesting that reactive oxygen species (ROS) might be involved in the genotoxic effect of alpha-Triol. Treatment with alpha-Triol increased the ROS production in CHO cells, which could be attenuated by catalase and SOD. Results in this study suggested, for the first time that alpha-Triol, causes genotoxic effect in an ROS-dependent manner. |
| Cholesterol-3-sulfate enhances phospholipase A2 activity by promoting interfacial binding Kinkaid, A. R., J. E. Voysey, et al. (1997), Biochem Soc Trans 25(3): 497S. |
| Cholesterol--a marker for multiple risk factors Schwandt, P. (1993), Dtsch Med Wochenschr 118(22): 846. |
| Cholesterol--a marker for multiple risk factors? A comparison between coronary disease and coronary health Winkelmann, B. R., B. Kaiser, et al. (1992), Dtsch Med Wochenschr 117(37): 1390-3. Abstract: Comparison was made in a cross-sectional study between 658 patients in whom coronary arteriography had shown (n = 304) or excluded coronary artery disease (CHD) (n = 354) and a clinically healthy group as controls (n = 1658), to assess possible risk factors. Patients aged 31-40 years with CHD had the highest total cholesterol levels (286 +/- 43 mg/dl) and the highest number of risk factors (3.6 +/- 0.9) compared to patients without CHD of the same age (204 +/- 30 mg/dl; 2.0 +/- 0.5) and healthy controls (216 +/- 45 mg/dl; 1.7 +/- 0.5) (P less than 0.001). In older patients with CHD, total cholesterol levels were lower (age group 61-70 years: 231 +/- 49 mg/dl), reaching about the same level as that of patients without CHD (232 +/- 54 mg/dl) or healthy controls of the same age (228 +/- 55 mg/dl). Furthermore, it was demonstrated that increased total cholesterol concentration can indicate the presence of other risk factors. It would thus appear that the level of total cholesterol in patients with CHD is decisively influenced by age and the presence of other risk factors. |
| Cholesterol--a model system to relate medical needs with analytical performance Wiebe, D. A. and J. O. Westgard (1993), Clin Chem 39(7): 1504-12; discussion 1512-3. Abstract: The evolution of cholesterol testing provides an example of a systematic approach that developed to relate the medical use of a laboratory test with the analytical performance requirements for that test. Laboratories today have the capability to perform cholesterol testing with the accuracy and precision necessary to meet medical needs. This statement can be made because (a) a standard diagnostic process has been established by the National Cholesterol Education Program; (b) an accuracy base is provided through a reference method that is readily available to manufacturers and laboratories; (c) the precision of analytical systems has been improved by manufacturers; (d) operating specifications for all such systems can be established, with statistical quality-control rules to ensure adequate within-run method performance; and (e) analytical performance is monitored by proficiency testing by using national quality requirements defined by CLIA '88 for acceptability. This cholesterol model provides a logical and scientific approach that should be applicable with other analytes to assure that the analytical performance of the laboratory test satisfies medical needs. |
| Cholesterol-armed cyclens for helical metal complexes offering chiral self-aggregation and sensing of amino acid anions in aqueous solutions Shinoda, S., T. Okazaki, et al. (2005), J Org Chem 70(5): 1835-43. Abstract: Cholesterol-armed cyclens worked as octadentate receptors for Na+, Ca2+, and Y3+ complexes in which four chiral cholesterol-functionalized sidearms were bundled and asymmetrically twisted above cyclen-metal complex platforms. Since the resulting helical metal complexes included chiral, hydrophobic cholesterol residues and charged, hydrophilic metal sites as well as asymmetric coordination geometries, they exhibited unique amphiphilic properties and provided chiral self-aggregates in aqueous solutions. Light scattering, fluorescence, and TEM characterizations demonstrated that Na+ complex with cholesterol-armed cyclen gave a particularly stable self-aggregate in aqueous solution and offered supramolecular environments effective for sensing and detection of amino acid anions. Various dansylamino acid derivatives (dansyl = 5-(dimethylamino)-1-naphthalenesulfonyl) were nicely accommodated in the helicate aggregates to give highly enhanced fluorescence signals, which could be detected by the naked eye at 10(-7) mol/L level. Their inclusion behaviors were analyzed by a Langmuir-type equation, indicating that enantiomer-selective inclusion occurred. MM/MD calculations and circular dichroism (CD) studies further suggested that cholesterol-armed cyclen helicates have chiral and hydrophobic cavities upon self-aggregation, in which the dansylamino acid anions were specifically accommodated. Since these helicates exhibited nonselective binding abilities in solvent extraction experiments of dansylamino acid anions, uncommon chiral recognition and sensing functions were generated by supramolecular alignments of the chiral metal helicates in the aqueous solutions. |
| Cholesterol-based pericardial effusion and aortic thromboembolism in a 9-year-old mixed-breed dog with hypothyroidism MacGregor, J. M., E. A. Rozanski, et al. (2004), J Vet Intern Med 18(3): 354-8. |
| Cholesterol-binding cytolytic protein toxins Alouf, J. E. (2000), Int J Med Microbiol 290(4-5): 351-6. Abstract: Cholesterol-binding cytolysins (CBCs) are a large family of 50- to 60-kDa single-chain proteins produced by 23 taxonomically different species of Gram-positive bacteria from the genera Streptococcus, Bacillus, Clostridium, Listeria and Arcanobacterium. Apart pneumolysin, which is an intracytoplasmic toxin, all the other toxins are secreted in the extracellular medium. Among the species producing CBCs, only L. monocytogenes and L. ivanovii are intracellular pathogens which grow and release their toxins in the phagocytic cells of the host. CBCs are lethal to animals and highly lytic toward eukaryotic cells, including erythrocytes. Their lytic and lethal properties are suppressed by sulfhydryl-group-blocking agents and reversibly restored by thiols or other reducing agents. These properties are irreversibly abrogated by very low concentrations of cholesterol and other 3beta-hydroxysterols. Membrane cholesterol is thought to be the toxin-binding site at the surface of eukaryotic cells. Toxins molecules bind as monomers to the membrane surface with subsequent oligomerization into arc-and ring-shaped structures surrounding large pores generated by this process. Thirteen structural genes of the toxins (all chromosomal) have been cloned and sequenced to date. The deduced primary structure of the proteins shows obvious sequence homology particularly in the C-terminal part and a characteristic common consensus sequence containing a unique Cys residue (ECTGLAWEWWR) near the C-terminus of the molecules (except pyolysin and intermedilysin). However, another Cys residue outside this undecapeptide and closer to the C-terminus occurs in ivanolysin. Genetic replacement of the Cys residue in the consensus undecapeptide by certain amino acids demonstrated that this residue was not essential for toxin function. Other residues in the undecapeptide have been mutagenized, particularly the Trp residues. One of these Trp appeared critical for lytic activity. The recent elucidation of the 3-D structure of perfringolysin O provided interesting information on the structure-activity relationship. The molecule was divided into four domains. Three domains are arranged in a row, giving an elongated shape. Domain 3 is covalently connected to the N-terminal domain 1 and packed laterally against domain 2. Membrane interaction of the monomer appears to be mediated by domain 4, while, oligomerization involves several sites scattered throughout the sequence. The Trp-rich region around the conserved Cys residue within domain 4 is assumed to conformationally adapt to cholesterol, and domain 3 is envisaged to move across the "hinge" by which it is connected to domain 1. |
| Cholesterol-containing circulating immune complexes in patients with cerebral arteriosclerosis and disorders of cerebral circulation Akopov, S. E., A. V. Nazarian, et al. (1991), Zh Nevropatol Psikhiatr Im S S Korsakova 91(7): 50-2. Abstract: A study was made of the level of circulating immune complexes (CIC) in patients with circulatory encephalopathy and brain infarction to find out the CIC level to be increased. The content of cholesterol in CIC was discovered to be also augmented, with that phenomenon being in agreement with the degree of atherosclerotic lesions to carotids. It has been shown that in patients with the increased content of cholesterol-containing CIC, the rise of platelet aggregation and blood coagulation is most remarkable. |
| Cholesterol-containing lactose derived neoglycolipids serve as acceptors for sialyltransferases from rat liver Golgi vesicles Pohlentz, G., A. Mokros, et al. (1996), Glycoconj J 13(2): 147-52. Abstract: The cholesterol-containing lactose derived neoglycolipids beta-Lactosylcholesterol, Cholesteryl-beta-lactosylpropane-1,3-diol, 3-Cholesteryl-1-beta-lactosylglycerol, 2-Cholesteryl-1-beta-lactosylglycerol, 2,3-Dicholesteryl-1-beta-lactosylglycerol, 1-Deoxy-1-cholesterylethanolaminolactitol, 1-Deoxy-1-cholesteryl (N-acetyl)-ethanolaminolactitol, 1-Deoxy-1-cholesterylphosphoethanolaminolactitol, and 1-Deoxy-1-cholesterylphospho (N-acetyl)-ethanolaminolactitol were synthesized and used as acceptors for sialytransferases from rat liver to Golgi vesicles. Relative activities with the neoglycolipids as acceptors varied from 28 to 163% compared to those obtained with the authentic acceptor lactosylceramide. Product identification by thin layer chromatography and fast atom bombardment mass spectrometry showed that the neoglycolipids yielded mono- and disialylated products. The results of competition experiments suggested that lactosylceramide and the neoglycolipids were sialylated by the same enzymes. |
| Cholesterol-dependent aggregation of amyloid beta-protein Yanagisawa, K. and K. Matsuzaki (2002), Ann N Y Acad Sci 977: 384-6. Abstract: One of the fundamental pathological processes of Alzheimer's disease (AD) is the aggregation of the amyloid beta-protein (Abeta). In the case of familial AD, the expression of genes responsible for this disease is likely to enhance aggregation of Abeta through its enhanced generation. However, there is no evidence to indicate thus far that in the case of sporadic AD, a major form of the disease, the generation of Abeta is altered. Thus, one could assume that the aggregation of Abeta in AD is induced by unknown posttranslational modification or by an altered clearance mechanism, or both. We previously identified a novel Abeta species in the human brain that exhibited early pathological changes of AD. This Aalpha is characterized by its tight binding to GM1 ganglioside (GM1). Based on its unique molecular characteristics, including its extremely high aggregation potential and altered immunoreactivity, we hypothesized that Abeta undergoes conformational alteration and acts as a seed for Abeta fibrillogenesis. In regard to the molecular mechanism underlying the formation of GM1-Abeta, we recently found that binding of Abeta to GM1 was facilitated in cholesterol-rich environments and, furthermore, it was dependent on the cholesterol-induced clustering of GM1 in the host membranes. Recently, increasing evidence indicates that cholesterol is a risk factor for AD development. The results of our current studies may provide a new insight into the molecular mechanism underlying the cholesterol-dependent development of AD. |
| Cholesterol-dependent association of caveolin-1 with the transducin alpha subunit in bovine photoreceptor rod outer segments: disruption by cyclodextrin and guanosine 5'-O-(3-thiotriphosphate) Elliott, M. H., S. J. Fliesler, et al. (2003), Biochemistry 42(26): 7892-903. Abstract: Evidence suggests that caveolins, 21-24 kDa cholesterol-binding proteins that generally reside in specialized detergent-resistant membrane microdomains, act as signaling scaffolds. Detergent-resistant membranes isolated from rod outer segments (ROS) have been previously shown to contain the photoreceptor G-protein, transducin. In this report we show, by subcellular fractionation, that caveolin-1 is an authentic component of purified ROS. We demonstrate that caveolin-1 in ROS almost exclusively resides in low-buoyant-density, cholesterol-rich, detergent-resistant membranes that can be disrupted by cholesterol depletion using methyl-beta-cyclodextrin (MCD). Cholesterol depletion was also observed to extract a pool of transducin alpha (Talpha) from ROS membranes. Immunoprecipitation with anti-caveolin-1 revealed the association of Talpha in the absence of Tbetagamma. Treatment of ROS with MCD resulted in a 2-fold decrease in recovery of Talpha in anti-caveolin-1 immunoprecipitates. This interaction was also completely disrupted when ROS were exposed to light in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS), a nonhydrolyzable GTP analogue. In addition, caveolin-1/Talpha association in the immune complex was disrupted by a peptide based on the primary sequence of the caveolin-1 scaffolding domain. Finally, we confirm the colocalization of caveolin-1 and Talpha in photoreceptors by immunofluorescence microscopy. These results strongly suggest that the association between Talpha and caveolin-1 occurs in cholesterol-rich, detergent-resistant membranes and is likely to be dependent upon the activation state of Talpha. |
| Cholesterol-dependent changes of glycosaminoglycan pattern in human aorta Kruse, R., M. Merten, et al. (1996), Basic Res Cardiol 91(5): 344-52. Abstract: Glycosaminoglycans are regular constituents of the arterial wall and essential for its structure and function. The arteriosclerosis-dependent changes of glycosaminoglycans were investigated, the degree of arteriosclerosis was monitored by the cholesterol content of the tissue. Histological characterization was achieved by electron microscopy. Total glycosaminoglycans were isolated from 33 delipidated segments of human aorta thoracica after exhaustive proteolytic digestion, and fractionated into the individual glycosaminoglycans by a multistep purification procedure. Chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), and hyaluronate (HA) were identified and quantified by chemical and enzymatic analysis. The concentration of total and individual glycosaminoglycans, expressed as mg/g delipidated dry weight of tissue, decreased significantly with increasing cholesterol content of tissue (p = 0.0005-0.005). The extent of decrease differed between the individual glycosaminoglycans as indicated by a shift in the CS/DS:HA:HS ratio from 47:32:21 in low cholesterol aortic segments to 59:29:12 in cholesterol-rich specimens. Determination of the relative molecular masses (Mr) revealed 58 kDa for CS/DS and 92 kDa for HS with a (statistically not significant) increase of the molecular mass of CS/DS and a decrease of HS with increasing cholesterol content. The copolymeric CS/DS glycosaminoglycans were disintegrated enzymatically into CS and DS containing fragments. A significantly higher relative DS content (p = 0.01) was found in cholesterol-rich arterial tissue (32.5%) as compared with low cholesterol tissue samples (28.8%). Cell culture experiments revealed that human arterial HS is able to inhibit the proliferation of cultured human arterial smooth muscle cells. The HS concentration required for a 30% inhibition of smooth muscle cell proliferation was in the same order as the tissue concentration of HS. This confirms the function of HS as an endogenous inhibitor of cell division and its impact for the development of atherosclerosis. |
| Cholesterol-dependent clustering of IL-2Ralpha and its colocalization with HLA and CD48 on T lymphoma cells suggest their functional association with lipid rafts Vereb, G., J. Matko, et al. (2000), Proc Natl Acad Sci U S A 97(11): 6013-8. Abstract: Immunogold staining and electron microscopy show that IL-2 receptor alpha-subunits exhibit nonrandom surface distribution on human T lymphoma cells. Analysis of interparticle distances reveals that this clustering on the scale of a few hundred nanometers is independent of the presence of IL-2 and of the expression of the IL-2R beta-subunit. Clustering of IL-2Ralpha is confirmed by confocal microscopy, yielding the same average cluster size, approximately 600-800 nm, as electron microscopy. HLA class I and II and CD48 molecules also form clusters of the same size. Disruption of cholesterol-rich lipid rafts with filipin or depletion of membrane cholesterol with methyl-beta-cyclodextrin results in the blurring of cluster boundaries and an apparent dispersion of clusters for all four proteins. Interestingly, the transferrin receptor, which is thought to be located outside lipid rafts, exhibits clusters that are only 300 nm in size and are less affected by modifying the membrane cholesterol content. Furthermore, transferrin receptor clusters hardly colocalize with IL-2Ralpha, HLA, and CD48 molecules (crosscorrelation coefficient is 0.05), whereas IL-2Ralpha colocalizes with both HLA and CD48 (crosscorrelation coefficient is between 0.37 and 0.46). This coclustering is confirmed by electron microscopy. The submicron clusters of IL-2Ralpha chains and their coclustering with HLA and CD48, presumably associated with lipid rafts, could underlie the efficiency of signaling in lymphoid cells. |
| Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid Kakio, A., S. I. Nishimoto, et al. (2001), J Biol Chem 276(27): 24985-90. Abstract: GM1 ganglioside-bound amyloid beta-protein (GM1/Abeta), found in brains exhibiting early pathological changes of Alzheimer's disease (AD) including diffuse plaques, has been suggested to be involved in the initiation of amyloid fibril formation in vivo by acting as a seed. To elucidate the molecular mechanism underlying GM1/Abeta formation, the effects of lipid composition on the binding of Abeta to GM1-containing lipid bilayers were examined in detail using fluorescent dye-labeled human Abeta-(1-40). Increases in not only GM1 but also cholesterol contents in the lipid bilayers facilitated the binding of Abeta to the membranes by altering the binding capacity but not the binding affinity. An increase in membrane-bound Abeta concentration triggered its conformational transition from helix-rich to beta-sheet-rich structures. Excimer formation of fluorescent dye-labeled GM1 suggested that Abeta recognizes a GM1 "cluster" in membranes, the formation of which is facilitated by cholesterol. The results of the present study strongly suggested that increases in intramembrane cholesterol content, which are likely to occur during aging, appear to be a risk factor for amyloid fibril formation. |
| Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains Wahrle, S., P. Das, et al. (2002), Neurobiol Dis 9(1): 11-23. Abstract: Buoyant membrane fractions containing presenilin 1 (PS1), an essential component of the gamma-secretase complex, and APP CTFbeta, a gamma-secretase substrate, can be isolated from cultured cells and brain by several different fractionation procedures that are compatible with in vitro gamma-secretase assays. Analysis of these gradients for amyloid beta protein (Abeta) and CTFgamma production indicated that gamma-secretase activity is predominantly localized in these buoyant membrane microdomains. Consistent with this localization, we find that gamma-secretase activity is cholesterol dependent. Depletion of membrane cholesterol completely inhibits gamma-secretase cleavage, which can be restored by cholesterol replacement. Thus, altering cholesterol levels may influence the development of Alzheimer's disease (AD) by influencing production and deposition of Abeta within cholesterol rich membrane microdomains. |
| Cholesterol-dependent generation of a seeding amyloid beta-protein in cell culture Mizuno, T., M. Nakata, et al. (1999), J Biol Chem 274(21): 15110-4. Abstract: Deposition of aggregated amyloid beta-protein (Abeta), a proteolytic cleavage product of the amyloid precursor protein (Abeta), is a critical step in the development of Alzheimer's disease(Abeta++). However, we are far from understanding the molecular mechanisms underlying the initiation of Abeta polymerization in vivo. Here, we report that a seeding Abeta, which catalyzes the fibrillogenesis of soluble Abeta, is generated from the apically missorted amyloid precursor protein in cultured epithelial cells. Furthermore, the generation of this Abeta depends exclusively on the presence of cholesterol in the cells. Taken together with mass spectrometric analysis of this novel Abeta and our recent study (3), it is suggested that a conformationally altered form of Abeta, which acts as a "seed" for amyloid fibril formation, is generated in intracellular cholesterol-rich microdomains. |
| Cholesterol-dependent generation of a unique amyloid beta-protein from apically missorted amyloid precursor protein in MDCK cells Mizuno, T., C. Haass, et al. (1998), Biochim Biophys Acta 1373(1): 119-30. Abstract: To investigate the implications of altered sorting of the beta-amyloid precursor protein (betaAPP) in the abnormal generation of amyloid beta-protein (Abeta), we characterized Abeta secreted from Madin-Darby canine kidney (MDCK) cells which had been stably transfected with a cDNA encoding the human beta-amyloid precursor protein (betaAPP695) with a 42 amino acid residue truncation at the carboxyl terminus (DeltaC). In DeltaC MDCK cells, the intracellular sorting of betaAPP is substantially altered to the apical surface. We detected an accumulation of a unique Abeta species in the apical compartment of DeltaC MDCK cell cultures. This unique Abeta was immunoprecipitated with 4G8 (a monoclonal antibody specific for Abeta17-24) and detected as a smear on Western blots, but was not immunoprecipitated with BAN50 (a monoclonal antibody raised against Abeta1-16). Interestingly, however, this Abeta species was readily immunoprecipitated with BAN50 upon treatment with formic acid. Furthermore, incubation of the DeltaC MDCK cells with compactin, an inhibitor of de novo cholesterol synthesis, or with filipin, a cholesterol-binding drug, resulted in marked changes in the characteristics of this Abeta species as follows: first, the Abeta was not observed as a smear on Western blots and second, the Abeta was immunoprecipitated with BAN50. The present results strongly suggest that an Abeta with unique molecular characteristics is generated from the missorted betaAPP in vivo in a cholesterol-dependent manner. |