| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content Mitter, D., C. Reisinger, et al. (2003), J Neurochem 84(1): 35-42. Abstract: Synaptophysin interacts with synaptobrevin in membranes of adult small synaptic vesicles. The synaptophysin/synaptobrevin complex promotes synaptobrevin to built up functional SNARE complexes thereby modulating synaptic efficiency. Synaptophysin in addition is a cholesterol-binding protein. Depleting the membranous cholesterol content by filipin or beta-methylcyclodextrin (beta-MCD) decreased the solubility of synaptophysin in Triton X-100 with less effects on synaptobrevin. In small synaptic vesicles from rat brain the synaptophysin/synaptobrevin complex was diminished upon beta-MCD treatment as revealed by chemical cross-linking. Mice with a genetic mutation in the Niemann-Pick C1 gene developing a defect in cholesterol sorting showed significantly reduced amounts of the synaptophysin/synaptobrevin complex compared to their homo- or heterozygous littermates. Finally when using primary cultures of mouse hippocampus the synaptophysin/synaptobrevin complex was down-regulated after depleting the endogenous cholesterol content by the HMG-CoA-reductase inhibitor lovastatin. Alternatively, treatment with cholesterol up-regulated the synaptophysin/synaptobrevin interaction in these cultures. These data indicate that the synaptophysin/synaptobrevin interaction critically depends on a high cholesterol content in the membrane of synaptic vesicles. Variations in the availability of cholesterol may promote or impair synaptic efficiency by interfering with this complex. |
| The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs Davis, H. R., Jr., K. K. Pula, et al. (2001), Metabolism 50(10): 1234-41. Abstract: Ezetimibe (SCH 58235) and SCH 48461 are potent cholesterol absorption inhibitors, which cause significant decreases in plasma cholesterol levels in cholesterol-fed animals and in humans with hypercholesterolemia. These compounds selectively block intestinal uptake and absorption of cholesterol. These cholesterol absorption inhibitors cause modest, inconsistent reductions in plasma cholesterol levels in animals fed cholesterol-free chow diets. Although, these compounds block cholesterol absorption and increase neutral sterol excretion, chow-fed animals compensate for the loss of biliary cholesterol by increasing hepatic cholesterol synthesis. Therefore, we determined the effect of SCH 48461 and ezetimibe in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors in chow-fed dogs. A synergistic reduction in plasma cholesterol was observed in chow-fed dogs given SCH 48461 (0.1 mg/kg/d) and the HMG CoA reductase inhibitor, lovastatin (5 mg/kg/d). Neither SCH 48461 nor lovastatin alone affected plasma cholesterol levels. Their combination for 14 days caused a 36% reduction in plasma cholesterol levels from 129 mg/dL to 83 mg/dL (P <.05). Ezetimibe (0.007 mg/kg/d) also caused synergistic reductions in plasma cholesterol levels in chow-fed dogs when combined with HMG CoA reductase inhibitors for 2 weeks (5 mg/kg lovastatin -50%; 2.5 mg/kg pravastatin -41%; 5 mg/kg fluvastatin -60%, and -30% with low doses of simvastatin and atorvastatin 1 mg/kg). The combination of this class of cholesterol absorption inhibitors with an HMG CoA reductase inhibitor should be very effective clinically at reducing plasma cholesterol levels, even with reduced dietary intake of cholesterol. |
| The temperature stability of mouse retroviruses depends on the cholesterol levels of viral lipid shell and cellular plasma membrane Beer, C., A. Meyer, et al. (2003), Virology 308(1): 137-46. Abstract: To delineate parameters contributing to the extracellular lifetime of retroviral vectors, we carried out stability tests of retroviruses derived from cell lines of different origin and kept under different cultivation conditions. Results show that amphotropic mouse retroviruses (MLV-A) derived from human and hamster cells exhibit 2- to 3-fold higher half-lives compared to retroviruses from mouse cells. Cultivation at 32 degrees C has been reported to yield high virus titers. However, the benefit of virus production in mouse cells at 32 degrees C is controversial. In our hands the cultivation temperature affected, hitherto not noticed, the half-life time of MLV-A. The 37/32 degrees C shift resulted in a 3-fold decrease of viral half-lifes compared to MLV-A released from mouse cells at 37 degrees C. Thus, MLV-A released at 37 degrees C is phenotypically different from MLV-A synthesized at 32 degrees C. Increased virus stability was inversely correlated with the level of cholesterol in the viral membrane. Finally, depletion of viral cholesterol in vitro resulted in intact virus with increased thermal stability. Thus, retrovirus lability depends on the host cell and parallels the cholesterol amount in the viral lipid shell. |
| The terpenoid theory of the origin of cellular life: the evolution of terpenoids to cholesterol Ourisson, G. and Y. Nakatani (1994), Chem Biol 1(1): 11-23. Abstract: Terpenoids have an apparently essential function in modern cellular membranes, reinforcing them against shear stresses. Primitive membranes could initially have been formed by simple terpenoids, and vesicles formed from these membranes may have evolved into progressively more complex units, more and more similar to protocells. |
| The thickness of cholesterol sulfate-containing membranes depends upon hydration Faure, C. and E. J. Dufourc (1997), Biochim Biophys Acta 1330(2): 248-52. Abstract: The ordering of 30 mol % cholesterol (CH) or cholesterol sulfate (CS) on chain deuterated dimyristoylphosphatidylcholine (DMPC) was investigated by 2H-NMR for different hydrations. It is found that: (i) hydration has merely no influence on chain order (chain length) for DMPC-cholesterol systems, (ii) in CS-containing mixtures chain order (length) is greater at low hydration (DMPC-to-water molar ratio, Ri, of 11.3) than in excess water (Ri approximately 500) and (iii) at low hydration the ordering is about the same for CS or CH-containing systems whereas it is not at high hydration. DMPC-CS bilayer thickness is therefore very sensitive to hydration. |
| The thyroid-cholesterol connection: an association between varying degrees of hypothyroidism and hypercholesterolemia in women Dickey, R. A. and S. Feld (2000), J Womens Health Gend Based Med 9(4): 333-6. |
| The TNT debate gives a lift to the debate about high-dose statins. Lower LDL cholesterol levels further reduce the cardiovascular risk Olsson, A. G. (2005), Lakartidningen 102(18-19): 1393-4. |
| The tolerability, pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA: Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability, in healthy volunteers Peck, R. W., R. Wiggs, et al. (1995), Eur J Clin Pharmacol 49(3): 243-9. Abstract: 447C88 (N-Heptyl-N'-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA: Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng.ml-1 (23 nM). It is poorly absorbed but 5 mg.kg-1.day-1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n = 8) or placebo (n = 4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n = 8) or placebo (n = 6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng.ml-1 and 9.0 ng.ml-1.h after 200 mg rising to 5.4 ng.ml-1 and 23.8 ng.ml-1.h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88. |
| The total and HDL-cholesterol levels in populations of St. Petersburg (Russia) and Leipzig (Germany) Plavinski, S. L., S. I. Plavinskaya, et al. (1999), Nutr Metab Cardiovasc Dis 9(4): 184-91. Abstract: BACKGROUND AND AIM: In the early 90s an increase in coronary heart disease (CHD) mortality in post-communist countries was observed. Based on the lipid theory of the pathogenesis of atherosclerosis, we looked to see whether these changes were accompanied by changes in blood lipid profiles and how lipid levels are related in a post-communist country with a relatively high standard of living (East Germany) and a country still facing economic troubles (Russia). METHODS AND RESULTS: This investigation was conducted in 1995-1997 by a cooperative program between the Department of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Leipzig, Germany and the Department of Biochemistry, Institute for Experimental Medicine, St. Petersburg, Russia. The Russian part of the study included 1646 subjects and the German part 3189 subjects. The blood lipids were measured using a dry-chemistry analyzer (Reflotron). Russian and German males had almost the same level of total cholesterol with a significantly lower level of HDL-C in Russians. A significantly lower level of HDL-C was also observed in Russian females. Differences were in range 2-3 mg/dl for males and 8-13 mg/dl for females. In St. Petersburg, almost 40% of all screened young males (age < 30 yr) had hypoalphacholesterolemia. In the St. Petersburg study carried out in 1986-1988, in age group 40-49 years around 6% of those screened had HDL-C lower than 35 mg/dl. In 1995-1997 this number increased to 36%. The number of subjects with HDL-C less than 30 mg/dl in 1986-1988 was only 2.4% and in 1995-1997, 12.3%. CONCLUSION: There is a dramatic decrease in HDL-C in the Russian population, probably due to the socioeconomic factors which began to develop after the fall of communist. |
| The total apolipoprotein B/LDL-cholesterol ratio dose not predict LDL particle size Tallis, G. A., M. D. Shephard, et al. (1995), Clin Chim Acta 240(1): 63-73. |
| The transport of low density lipoprotein-derived cholesterol to the plasma membrane is defective in NPC1 cells Wojtanik, K. M. and L. Liscum (2003), J Biol Chem 278(17): 14850-6. Abstract: Niemann-Pick disease type C (NPC) is characterized by lysosomal storage of cholesterol and gangliosides, which results from defects in intracellular lipid trafficking. Most studies of NPC1 have focused on its role in intracellular cholesterol movement. Our hypothesis is that NPC1 facilitates the egress of cholesterol from late endosomes, which are where active NPC1 is located. When NPC1 is defective, cholesterol does not exit late endosomes; instead, it is carried along to lysosomal storage bodies, where it accumulates. In this study, we addressed whether cholesterol is transported from endosomes to the plasma membrane before reaching NPC1-containing late endosomes. Our study was conducted in Chinese hamster ovary cell lines that display the classical NPC biochemical phenotype and belong to the NPC1 complementation group. We used three approaches to test whether low density lipoprotein (LDL)-derived cholesterol en route to NPC1-containing organelles passes through the plasma membrane. First, we used cyclodextrins to measure the arrival of LDL cholesterol at the plasma membrane and found that the arrival of LDL cholesterol in a cyclodextrin-accessible pool was significantly delayed in NPC1 cells. Second, the movement of LDL cholesterol to NPC1-containing late endosomes was assessed and found to be normal in Chinese hamster ovary mutant 3-6, which exhibits defective movement of plasma membrane cholesterol to intracellular membranes. Third, we examined the movement of plasma membrane cholesterol to the endoplasmic reticulum and found that this pathway is intact in NPC1 cells, i.e. it does not pass through NPC1-containing late endosomes. Our data suggest that in NPC1 cells LDL cholesterol traffics directly through endosomes to lysosomes, bypassing the plasma membrane, and is trapped there because of dysfunctional NPC1. |
| The treatment of coronary heart disease: an update. Part 3: Statins beyond cholesterol lowering Kolovou, G. (2001), Curr Med Res Opin 17(1): 34-7. Abstract: Statins may have additional properties beyond diminishing low-density lipoprotein (LDL) cholesterol levels. These actions could reduce the risk of vascular events. For example, these lipid lowering drugs act on the vascular endothelium, smooth muscle, haemostatic factors and the vessel wall. There are several differences in how statins act on these systems. These observations, in turn, lead to the conclusion that all statins may not be equally effective in terms of vascular disease prevention. |
| The tryptophan-rich region of HIV gp41 and the promotion of cholesterol-rich domains Epand, R. F., B. G. Sayer, et al. (2005), Biochemistry 44(14): 5525-31. Abstract: The peptide N-acetyl-KWASLWNWFNITNWLWYIK-amide has a sequence that corresponds to the juxtamembrane region of the HIV-1 gp41 fusion protein. We have studied how cholesterol modulates the interaction of this peptide with membranes containing cholesterol using differential scanning calorimetry, circular dichroism, fluorescence spectroscopy, and nuclear magnetic resonance. We find that this peptide is less able to sequester cholesterol into domains than is N-acetyl-LWYIK-amide. On the other hand, the peptide N-acetyl-LASWIK-amide, which corresponds to a segment of HIV-2 and SIV gp41 fusion proteins, has intermediate potency between N-acetyl-KWASLWNWFNITNWLWYIK-amide and N-acetyl-LWYIK-amide in forming areas enriched in cholesterol, even though it does not have a cholesterol recognition/interaction amino acid consensus sequence (CRAC). We suggest that the difference between HIV-1 and HIV-2 in their requirements for glycosphingolipids in determining their tropism is related to their difference in partitioning to cholesterol-rich domains in biological membranes. |
| The type of dietary fat alters the hepatic uptake and biliary excretion of cholesterol from chylomicron remnants Lambert, M. S., M. A. Avella, et al. (2000), Br J Nutr 83(4): 431-8. Abstract: The consumption of fat-enriched diets may alter the uptake and metabolism of chylomicron remnant cholesterol by the liver. To test this hypothesis, 3Hcholesterol-labelled chylomicron remnants derived from different dietary fats were studied in perfused livers both from rats fed on diets enriched in the corresponding fats and from rats fed on a low-fat diet. Livers from rats fed on each of the fat-enriched diets removed similar amounts (34-40%) of the 3Hcholesterol-labelled remnants added, whereas livers from rats fed on the low-fat diet removed significantly more labelled fish-oil and butter-fat remnants than olive-, maize- or palm-oil remnants. Significantly more remnant 3Hcholesterol was secreted into the perfusate HDL by livers from rats fed on the olive-oil, fish-oil and butter-fat diets when compared with those from rats fed on the low-fat diet or the maize-oil diet. Furthermore, the excretion of remnant 3Hcholesterol via the bile acid was increased by the olive-, maize-, palm- or fish-oil diets, and decreased by the butter-fat diet when compared with the low-fat diet, although the 3Hbile acid excreted remained less on saturated fat diets. This investigation shows that the hepatic uptake and subsequent metabolism of cholesterol from chylomicron remnants is influenced by the type of fat in the diet as well as the fatty acid composition of the particles themselves, and may help to explain some of the hyper- and hypocholesterolaemic effects of saturated and unsaturated fatty acids. |
| The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia Heath, K. E., V. Gudnason, et al. (1999), Atherosclerosis 143(1): 41-54. Abstract: In a genetically heterogeneous group of 109 patients with a clinical diagnosis of heterozygous familial hypercholesterolaemia (FH), the influence of gender, apolipoprotein (apo) E genotype and the type of molecular defect in the LDL-receptor (LDLR) gene on the reduction of plasma LDL-cholesterol levels to treatment with a HMG-CoA reductase inhibitor (simvastatin) were studied. Response was determined as the percentage fall in LDL-cholesterol from untreated levels and as the proportion of patients where levels fell below 4.9 or 4.1 mmol/l. Of the patients, 86 individuals had tendon xanthomata (TX+) and a diagnosis of 'definite' FH and these individuals presented with a significantly higher untreated LDL-cholesterol compared to the 23 individuals who did not have xanthomas (TX-) and a diagnosis of 'probable' FH (8.14+/-0.19 vs. 6.81+/-0.25, P= 0.001). Overall, HMG-CoA reductase inhibitor doses of 10, 20 or 40 mg/day resulted in a significant fall of LDL-cholesterol levels of 29, 39 and 49%, but at all doses those with TX had significantly higher levels than those without, and significantly fewer TX + patients achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l than the TX - group (P < 0.05 at each dose). In the TX+ group the response to treatment was of similar magnitude in men and women and in patients with different apoE genotype. In the 'probable' FH probands only three mutations were identified (detection rate 13%), one in the LDLR gene and two in the APOB gene, a detection rate significantly lower (P= 0.02) than in the 'definite' FH probands where 28 mutations were detected (detection rate 37%). In the TX + patients where no mutation was detected, treatment resulted in a greater proportion achieving LDL-cholesterol levels below 4.9 and 4.1 mmol/l compared to those with any LDLR mutation, this difference was close to statistical significance at the 4.9 mmol/l threshold at 10 mg/day (41 vs. 13%, P = 0.058). For the 14 patients with an LDLR mutation that was predicted to be 'severe', fewer achieved LDL-cholesterol levels below 4.9 or 4.1 mmol/l at each dosage compared to the 16 individuals with 'mild' mutations, and this difference was statistically significant at the maximal dosage of 40 mg/day (P = 0.018). Thus although characterisation of the molecular defect in FH patients may not be relevant to their immediate clinical management, those with a particular mutation may need more aggressive lipid-lowering treatment to reach LDL-cholesterol levels recommended to reduce the risk of coronary heart disease (CHD). |
| The ultrastructure of cholesterol granuloma of the middle ear: an electron microscope study. The Journal of Laryngology and Otology, 1979; Vol. 93, pp. 433-442 Friedmann, I. and M. D. Graham (2002), J Laryngol Otol 116(11): 877-81. |
| The undertreatment of LDL-cholesterol: addressing the challenge Pearson, T. A. (2000), Int J Cardiol 74 Suppl 1: S23-8. Abstract: Patients with dyslipidemia are at increased risk of coronary heart disease (CHD), while treatment to reduce low density lipoprotein cholesterol (LDL-C) concentrations lessens this risk. Consequently, the Lipid Treatment Assessment Project (L-TAP) was undertaken in the US to determine the extent to which primary care practitioners utilize lipid-lowering therapy and to evaluate the success of current therapeutic regimens, using the National Cholesterol Education Program (NCEP) guidelines as therapeutic targets. The L-TAP study, initiated in 1996 and completed in February 1997, recorded LDL-C levels in 4888 patients from 619 US practices. All patients had received lipid-lowering therapy for at least 3 months. The primary care practitioners involved in the study were questioned about the NCEP guidelines and the results confirmed that these physicians were representative of primary care practitioners in the USA. The 4888 patients were categorized according to risk: patients with <2 risk factors (RFs) but no CHD, those with >/=2 RFs but no CHD and patients with confirmed CHD. Overall, only 38% of the patients attained LDL-C target levels or had values lower than these goals. The greater the number of RFs, the lower the proportion of patients achieving target levels. LDL-C targets were less often attained in patients receiving dietary therapy only compared with those receiving lipid lowering drug treatment. However, there was good correlation between the success of treatment and both receipt of and compliance with dietary instruction. In conclusion, a large proportion of dyslipidemic patients who are being treated in primary care are not achieving NCEP target LDL-C levels. |
| The uptake of cholesterol at the small-intestinal brush border membrane is inhibited by apolipoproteins Boffelli, D., S. Compassi, et al. (1997), FEBS Lett 411(1): 7-11. Abstract: The uptake of free and esterified cholesterol at the brush border membrane is protein-mediated. Here we show that this sterol uptake is effectively inhibited by exchangeable serum apolipoproteins. Binding of the apolipoprotein to the brush border membrane mediates the inhibitory effect. Evidence is presented to show that the structural motif responsible for the inhibition is the amphipathic alpha-helix. |
| The US National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) prevalence of the metabolic syndrome in a Chinese population Thomas, G. N., S. Y. Ho, et al. (2005), Diabetes Res Clin Pract 67(3): 251-7. Abstract: To assess the prevalence of the metabolic syndrome disease cluster in the Hong Kong Chinese population we applied the US National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) guidelines. This was present if > or =3 of the following conditions were present: Hypertension (> or =130/85 mmHg); fasting plasma glucose was > or =6.1 mmol/L; fasting plasma triglycerides > or =1.69 mmol/L; fasting HDL-cholesterol <1.04 or <1.29 mmol in males and females, respectively; or subjects were receiving treatment for their condition; waist circumference >88 or 102 cm (Asian WHO criteria > or =80 or 90 cm) in females and males, respectively. A total of 16.7% (17.1 (95%CI 15.7-18.5)% age and gender-adjusted) of the 2893 subjects had the metabolic syndrome. The prevalence of having at least 2, 3, 4 or 5 components was 34.5, 16.7, 6.4 and 1.4%, respectively. The prevalence increased from 3.1% in those aged 25-29 years to 41.0% in those aged over 70 years. Using the 2001 Census, 880,499 Hong Kong residents would have the metabolic syndrome. If the WHO recommended waist circumference for Asians is used, the age and gender-adjusted prevalence is significantly higher at 21.2% (21.9 (95%CI 20.4-23.4)%). In summary, the high prevalence of the metabolic syndrome in adult Hong Kong Chinese, particularly in the elderly, forewarns a rapidly increasing problem in Mainland China, and other Asian populations, which may have overwhelming public health ramifications. |
| The use of desk-top cholesterol analysers in general practice Summerton, A. M. and N. Summerton (1995), Public Health 109(5): 363-7. Abstract: An examination of the use of desk-top cholesterol analysers was performed within 10 practices in Kirklees, West Yorkshire. The survey entailed a questionnaire survey of the principal users of desk-top cholesterol analysers and the analysis of two laboratory quality control samples. The majority of practices used Boehringer Lipotrend, with frequency of use varying from < 5 tests/week to a maximum of 20/week. Training by manufacturers was absent in four practices. The maintenance of analysers was inadequate in seven practices as was quality control in five practices. Analysis of laboratory quality control samples showed about 50% of results within 0.5 mmol/l of mean, but 20.6% differed from mean by > 1 mmol/l. The coefficients of variation were 18% and 20% respectively. The use of desk-top cholesterol analysers is increasing in general practice, but improvements in training and quality control are necessary to ensure precise and accurate results with near-patient testing. |