| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol alert Smith, I. K. (2001), Time 157(21): 90. |
| Cholesterol alterations in young dystrophic mice Logan, D. M. and K. H. Tsang (1992), Mol Cell Biochem 110(1): 55-64. Abstract: Cholesterol and cholesteryl ester concentrations and cholesteryl ester fatty acid substituents have been measured during the first 10 weeks of life in tissues of normal and dystrophic mice. In normal Swiss and 129ReJ(+/?) mice the concentrations of both cholesterol and cholesteryl esters remain essentially constant in liver, increase in brain and fall sharply in both thigh (mixed fiber type muscles) and chest muscles (predominantly slow oxidative muscles) over this period. In all cases the concentration of free cholesterol exceeds that of esterified cholesterol. In dystrophic mice, similar patterns are found in brain and liver. In both thigh and chest muscles, however, the developmental pattern is significantly different. After an initial decrease the concentrations of cholesterol and cholesteryl esters increase rapidly with the largest increase occurring in the concentration of cholesteryl esters which by 10 weeks of age exceeds the concentration of cholesterol in chest muscle. During the same period the pattern of esterified fatty acids changes gradually in dystrophic tissues towards an increasing ratio of unsaturated/saturated fatty acids. By 10 weeks of age this ratio is significantly higher in dystrophic tissues than normal in all tissues tested. |
| Cholesterol alters the binding of Ca2+ channel blockers to the membrane lipid bilayer Mason, R. P., D. M. Moisey, et al. (1992), Mol Pharmacol 41(2): 315-21. Abstract: X-ray diffraction and equilibrium binding techniques were used to study the effect of cholesterol on membrane binding of the charged 1,4-dihydropyridine (DHP) Ca2+ channel antagonist amlodipine and uncharged isradipine, nimodipine, and nitrendipine. Increases in membrane cholesterol content resulted in a marked decrease in DHP binding to cardiac phospholipid membranes, as expressed by the equilibrium partition coefficient (Kpmem). Between a 0:1 and 0.3:1 cholesterol to phospholipid mole ratio, the Kp(mem) values for isradipine, nimodipine, and nitrendipine decreased by greater than 50%, whereas that for amlodipine decreased by only 10%. Electron density profiles calculated from the X-ray diffraction data showed that the time-averaged locations for the DHPs and cholesterol in the membrane overlap, leading to the conclusion that the addition of cholesterol alters the lipid bilayer hydrocarbon core structure in a manner that makes drug partitioning into the membrane less energetically favorable. These data support the idea that drug interactions with the anisotropic membrane environment are complex and may be greatly influenced by cholesterol composition. This effect of cholesterol was also observed for phenylalkylamine (verapamil) and benzothiazepine (diltiazem) Ca2+ channel blockers. The DHP amlodipine had the highest membrane partition coefficient (Kpmem greater than 10(4) and the slowest rate of dissociation and was affected least by membrane cholesterol content. The combination of electrostatic and hydrophobic bonding between amlodipine and membrane phospholipid may explain the high affinity of this drug for the membrane bilayer with normal and elevated cholesterol. The results of this study show that cholesterol content differentially affects the membrane-binding properties of the charged DHP amlodipine, compared with other Ca2+ channel blockers. These data help explain the biological distribution of these drugs and the distinct pharmacokinetics of amlodipine versus other Ca2+ channel blockers. |
| Cholesterol alters the interaction of glycosphingolipid GM3 with alpha5beta1 integrin and increases integrin-mediated cell adhesion to fibronectin Gopalakrishna, P., N. Rangaraj, et al. (2004), Exp Cell Res 300(1): 43-53. Abstract: Integrins bind to their ligand in the extracellular matrix (ECM), such as fibronectin (FN), through a specific interaction between the amino acid motifs in the ligand, and binding sites in the extracellular domains of the integrin molecule generated jointly by its alpha and beta subunits. It has been proposed that membrane cholesterol and glycosphingolipids (GSLs) can regulate integrin-ECM interactions and it has been demonstrated that increased membrane cholesterol leads to increased cell adhesion to FN. Here, we have shown that a specific glycosphingolipid GM3 binds directly to alpha5beta1 integrin and an increase in membrane cholesterol results in the redistribution of GM3-associated alpha5beta1 integrin molecules specifically on the surface that is in contact with the substratum. Our results suggest that GM3-associated alpha5beta1 integrins bind less avidly to FN than GM3-free integrins and that cholesterol and GM3 play an interdependent role in the distribution of alpha5beta1integrin molecules in the membrane and regulation of cell adhesion. |
| Cholesterol amperometric biosensor based on cytochrome P450scc Shumyantseva, V., G. Deluca, et al. (2004), Biosens Bioelectron 19(9): 971-6. Abstract: A screen-printed enzyme electrode based on flavocytochrome P450scc (RfP450scc) for amperometric determination of cholesterol has been developed. A one-step method for RfP450scc immobilization in the presence of glutaraldehyde or by entrapment of enzyme within a hydrogel of agarose is discussed. The sensitivity of the biosensor based on immobilization procedures of flavocytochrome P450scc by glutaric aldehyde is 13.8 nA microM(-1) and the detection limit is 300 microM with a coefficient of linearity 0.98 for cholesterol in the presence of sodium cholate as detergent. The detection limits and the sensitivity of the agarose-based electrode are 155 microM and 6.9 nA microM(-1) with a linearity coefficient of 0.99. For both types of electrodes, the amperometric response to cholesterol in the presence of detergent was rather quick (1.5-2 min). |
| Cholesterol anarchy? Agner, E. (1990), Ugeskr Laeger 152(44): 3269. |
| Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and Insigs Adams, C. M., J. Reitz, et al. (2004), J Biol Chem 279(50): 52772-80. Abstract: The current paper demonstrates that cholesterol and its hydroxylated derivative, 25-hydroxycholesterol (25-HC), inhibit cholesterol synthesis by two different mechanisms, both involving the proteins that control sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that activate genes encoding enzymes of lipid synthesis. Using methyl-beta-cyclodextrin as a delivery vehicle, we show that cholesterol enters cultured Chinese hamster ovary cells and elicits a conformational change in SREBP cleavage-activating protein (SCAP), as revealed by the appearance of a new fragment in tryptic digests. This change causes SCAP to bind to Insigs, which are endoplasmic reticulum retention proteins that abrogate movement of the SCAP.SREBP complex to the Golgi apparatus where SREBPs are normally processed to their active forms. Direct binding of cholesterol to SCAP in intact cells was demonstrated by showing that a photoactivated derivative of cholesterol cross-links to the membrane domain of SCAP. The inhibitory actions of cholesterol do not require the isooctyl side chain or the Delta5-double bond of cholesterol, but they do require the 3beta-hydroxyl group. 25-HC is more potent than cholesterol in eliciting SCAP binding to Insigs, but 25-HC does not cause a detectable conformational change in SCAP. Moreover, a photoactivated derivative of 25-HC does not cross-link to SCAP. These data imply that cholesterol interacts with SCAP directly by inducing it to bind to Insigs, whereas 25-HC works indirectly through a putative 25-HC sensor protein that elicits SCAP-Insig binding. |
| Cholesterol and 25-hydroxycholesterol retention in specimens of liver and aorta prepared for electron microscopy. I. Standard fixation methods and metabolism of the labeled sterols Fornas, E., J. Renau-Piqueras, et al. (1993), Lipids 28(10): 923-8. Abstract: In the present work, several preparatory procedures commonly used for electron microscopy (EM) were evaluated as to their ability to preserve cholesterol (CHO) and CHO derivatives in tissue. We also determined in several rat tissues to what extent the sterols used as tracers are metabolized. Sprague-Dawley rats were injected intraperitoneally with 1 alpha,2 alpha(n)-3Hcholesterol (3HCHO) and 25-hydroxy-26,27-3Hcholesterol (3H25-OH-CHO). Lipids of the liver, aorta and brain were extracted one and five days after injection, and the distribution of the labeled lipids was followed by thin-layer chromatography. When labeled CHO was injected as tracer, most of the radioactivity remained associated with the CHO fraction. When 25-hydroxycholesterol (25-OH-CHO) was used, we found that it was mostly metabolized to yield more polar compounds. Our results show that the loss of CHO and CHO derivatives from tissues depends not only on the preparatory procedure used for EM, but also on the type of tissue studied. |
| Cholesterol and 25-hydroxycholesterol retention in specimens of liver and aorta prepared for electron microscopy. II. Effect of filipin, osmium, digitonin and saponin Fornas, E., J. Renau-Piqueras, et al. (1993), Lipids 28(10): 929-35. Abstract: Sprague-Dawley rats were injected intraperitoneally with 1 alpha, 2 alpha(n)-3Hcholesterol or 25-hydroxy-26,27-3Hcholesterol, and one and five days later liver and aortic tissues were fixed. The extent to which these sterols were lost from the tissues during preparation for electron microscopy (EM) was examined utilizing different fixation procedures and various protective agents. Radioactive tracers, scintillation counting and standard EM techniques were used. Although most of the procedures examined caused major lipid losses, useful fixation procedures that allow retention of cholesterol or 25-hydroxy-cholesterol in liver and aortic tissues were found and are described here. |
| Cholesterol and 27-hydroxycholesterol 7 alpha-hydroxylation: evidence for two different enzymes Martin, K. O., K. Budai, et al. (1993), J Lipid Res 34(4): 581-8. Abstract: The use of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for solubilizing cholesterol and 27-hydroxycholesterol has led to a study of their rates of 7 alpha-hydroxylation in microsomal preparations from hamster liver and HepG2 cells. Addition of the vehicle alone to the cholesterol 7 alpha-hydroxylase assay always caused a several-fold increase in activity. Preloading the vehicle with cholesterol further augmented the rate of 7 alpha-hydroxycholesterol formation. Preloading the vehicle with 27-hydroxycholesterol or 27-hydroxycholestanol (molar ratio 1/1.2) minimally decreased cholesterol 7 alpha-hydroxylase activity (-12%), compared with preloading with cholestanol (-50%), a known competitive inhibitor of the enzyme. Microsomes from hamster liver yielded rates of 7 alpha,27-dihydroxcholesterol formation of 1.5 to 3.0 nmol/min per mg protein, compared with 0.3 nmol/min per mg protein for 7 alpha-hydroxycholesterol. Although cholesterol and cholestanol had minimal effects on the rate of 7 alpha-hydroxylation of 27-hydroxycholesterol, addition of an approximately equimolar amount of 27-hydroxycholestanol inhibited the rate of formation by 65%. Attempts to separate and identify the two C-27 sterol 7 alpha-hydroxylases chromatographically led to the finding that Emulgen 913 selectively inactivates 7 alpha-hydroxylation of 27-hydroxycholesterol. These results indicate that the metabolic pathway for bile acid synthesis from 27-hydroxycholesterol is not governed by cholesterol 7 alpha-hydroxylase. |
| Cholesterol and Abeta aggregation Yanagisawa, K. (2003), Pharmacopsychiatry 36 Suppl 2: S127-9. Abstract: Regarding deposition of amyloid beta-protein (Abeta) in brains with Alzheimer's disease (AD), we previously identified a novel Abeta species that strongly binds to GM1 ganglioside (GM1) in human brains that exhibit early pathological changes of AD. We hypothesized that Abeta undergoes conformational alteration through its binding to GM1 and acts as a seed. We recently found that an increase in the cholesterol concentration in host membranes markedly accelerates Abeta binding to GM1. We then investigated whether the cholesterol concentration in neuronal membranes could be altered under biological conditions that are associated with risk factors for AD development. We attempted to determine the distribution of cholesterol in the synaptic plasma membranes (SPMs) of human apolipoprotein E (apoE)-knock-in mice and found that the cholesterol concentration in the exofacial leaflet of SPMs of the human apoE4-knock-in mice was approximately twice that of human apoE3-knock-in mice. The results of our studies suggest that an increase in the cholesterol concentration in the neuronal membranes accelerates Abeta aggregation through the formation of an endogenous seed. |
| Cholesterol and age-related macular degeneration: is there a link? van Leeuwen, R., C. C. Klaver, et al. (2004), Am J Ophthalmol 137(4): 750-2. Abstract: PURPOSE: To examine the relation among serum cholesterol, apolipoprotein E genotype (APOE), and the risk of early and late age-related macular degeneration (AMD). DESIGN: The Rotterdam Study, a population based prospective cohort study. METHODS: Serum levels of total and high-density lipoprotein (HDL) cholesterol as well as APOE genotype were determined at baseline. Of 3,944 subjects, 400 were diagnosed with incident early and late AMD after a mean follow-up of 5.2 years. RESULTS: Serum HDL, but not total, cholesterol was associated with an increased risk of AMD (odds ratio/SD, 1.20; 95% confidence interval; 1.06-1.35). The association remained unchanged after adjustment for APOE genotype. When stratifying for APOE genotype, the association was strongest in persons with the e 4 allele; an inverse association seemed to be present for e 2 carriers. CONCLUSION: Elevated HDL but not total cholesterol is associated with an increased risk of AMD. Apolipoprotein E genotype does not explain this association but may be an effect modifier. |
| Cholesterol and aggression Goodman, J., K. W. Davidson, et al. (1997), J Am Acad Child Adolesc Psychiatry 36(3): 303-4. |
| Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study Schatz, I. J., K. Masaki, et al. (2001), Lancet 358(9279): 351-5. Abstract: BACKGROUND: A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality. METHODS: Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models. FINDINGS: Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36). INTERPRETATION: We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people. |
| Cholesterol and all-cause mortality in Honolulu Cuchel, M. and D. J. Rader (2001), Lancet 358(9296): 1903-4; author reply 1906. |
| Cholesterol and all-cause mortality in Honolulu Fernandez-Real, J. M. and W. Ricart (2001), Lancet 358(9296): 1906-7. |
| Cholesterol and all-cause mortality in Honolulu Law, M. and N. J. Wald (2001), Lancet 358(9296): 1904; author reply 1906. |
| Cholesterol and all-cause mortality in Honolulu Ravnskov, U. (2001), Lancet 358(9296): 1907. |
| Cholesterol and all-cause mortality in Honolulu Tilvis, R. S., T. E. Strandberg, et al. (2001), Lancet 358(9296): 1904-5; author reply 1906. |
| Cholesterol and all-cause mortality in Honolulu Weverling-Rijnsburger, A. W., G. J. Blauw, et al. (2001), Lancet 358(9296): 1905-6. |