| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of cholesterol on surface activity and surface topography of spread surfactant films Diemel, R. V., M. M. Snel, et al. (2002), Biochemistry 41(50): 15007-16. Abstract: Pulmonary surfactant forms a monolayer of lipids and proteins at the alveolar air/liquid interface. Although cholesterol is a natural component of surfactant, its function in surface dynamics is unclear. To further elucidate the role of cholesterol in surfactant, we used a captive bubble surfactometer (CBS) to measure surface activity of spread films containing dipalmitoylphosphatidylcholine/1-palmitoyl-2-oleoylphosphatidylcholine/1-p almitoyl-2-oleoylphosphatidylglycerol (DPPC/POPC/POPG, 50/30/20 molar percentages), surfactant protein B (SP-B, 0.75 mol %), and/or surfactant protein C (SP-C, 3 mol %) with up to 20 mol % cholesterol. A cholesterol concentration of 10 mol % was optimal for reaching and maintaining low surface tensions in SP-B-containing films but led to an increase in maximum surface tension in films containing SP-C. No effect of cholesterol on surface activity was found in films containing both SP-B and SP-C. Atomic force microscopy (AFM) was used, for the first time, to visualize the effect of cholesterol on topography of SP-B- and/or SP-C-containing films compressed to a surface tension of 22 mN/m. The protrusions found in the presence of cholesterol were homogeneously dispersed over the film, whereas in the absence of cholesterol the protrusions tended to be more clustered into network structures. A more homogeneous dispersion of surfactant lipid components may facilitate lipid insertion into the surfactant monolayer. Our data provide additional evidence that natural surfactant, containing SP-B and SP-C, is superior to surfactants lacking one of the components, and furthermore, this raises the possibility that the cholesterol found in surfactant of warm-blooded mammals does not have a function in surface activity. |
| Effects of cholesterol on the function and thermotropic properties of pure UDP-glucuronosyltransferase Rotenberg, M. and D. Zakim (1991), J Biol Chem 266(7): 4159-61. Abstract: The effects of cholesterol on the activity and thermal properties of a pure, delipidated isoform of UDP-glucuronosyltransferase were examined after incorporation of enzyme into unilamellar bilayers of distearoylphosphatidylcholine (DSPC) or dioleoylphosphatidylcholine (DOPC). Cholesterol, in bilayers of DSPC, decreased enzyme activity and lowered the temperature (from 37 to 30 degrees C) for a reversible transition from the active form of the enzyme to a less active form. These effects could be separated from each other in that the effect on reversible inactivation of the enzyme occurred at lower concentrations of cholesterol than the effect on activity of the active form of the enzyme. In addition, cholesterol in bilayers of DSPC stabilized UDP-glucuronosyltransferase against irreversible thermal inactivation. The extent of stabilization increased with increasing concentration of cholesterol in the bilayers. The effects of cholesterol on UDP-glucuronosyltransferase depended, however, on the nature of the bilayer containing cholesterol. Cholesterol had small effects, if any, on the properties of UDP-glucuronosyltransferase in bilayers of DOPC. |
| Effects of cholesterol on the interaction of Ca2(+)-ATPase with 1-palmitoyl-2-oleoylphosphatidylethanolamine. An FTIR study Yang, J., G. L. Anderle, et al. (1990), Biochim Biophys Acta 1021(1): 27-32. Abstract: Ca2(+)-ATPase from rabbit skeletal muscle has been isolated, purified, and reconstituted into vesicles containing binary mixtures of 1-palmitoyl-2-oleoylphosphatidylethanolamine (POPE)/cholesterol. Fourier transform infrared spectroscopy (FTIR) was used to investigate the effect of protein on the thermotropic behavior of POPE in these reconstituted ternary complexes. The CH2 symmetric stretching modes of the phospholipid acyl chains near 2850 cm-1 served as an index of the melting process. The thermotropic transition of the POPE component in a 103:12:1 (POPE/cholesterol/Ca2(+)-ATPase) complex was shifted to lower temperatures compared with a protein-free binary lipid mixture of the same relative proportions. When combined with differential scanning calorimetric (DSC) data for the binary (POPE/cholesterol) lipid systems, this observation suggests that Ca2(+)-ATPase preferentially sequesters 15-35 molecules of POPE from the lipid mixture and therefore excludes cholesterol from its immediate environment. Higher levels of cholesterol in ternary complexes progressively eliminate the cooperative POPE melting event. |
| Effects of cholesterol on the lamellar and the inverted hexagonal phases of dielaidoylphosphatidylethanolamine Takahashi, H., K. Sinoda, et al. (1996), Biochim Biophys Acta 1289(2): 209-16. Abstract: Effects of cholesterol on the lamellar and the inverted hexagonal (HII) phases of dielaidoylphosphatidylethanolamine (DEPE) were studied by means of not only differential scanning calorimetry (DSC) but also simultaneous X-ray diffraction and DSC (XDDSC). XDDSC shows that structural changes are related to thermotropic events of the mixtures. Addition of cholesterol to DEPE induces to broaden the transition from the lamellar gel (L beta) to lamellar liquid-crystalline (L alpha) phase. In fact, in the broad transition region, a coexistence of two lamellar X-ray diffraction peaks of the L beta and L alpha phases take place. In samples containing above 30 mol% cholesterol, no peak at the L beta-L alpha phase transition was observed in the DSC thermogram. On the other hand, cholesterol causes biphasic effects on the L alpha-HII phase transition: At low cholesterol concentrations below 20 mol%, the incorporation of cholesterol reduces the transition temperature and at high cholesterol concentrations about 30 mol%, the transition temperature increases by addition of cholesterol. Based upon the results of X-ray diffraction, the thermal expansion coefficients of lattice spacings, i.e., the temperature dependence of lattice spacings, were calculated in each phase. Addition of cholesterol reduces the thermal expansion coefficients of the lamellar phases and, in contrast, increases that of the HII phase. From the above results it is suggested that cholesterol in cell membranes works in keeping the bilayer membrane nature notwithstanding the change of external conditions. |
| Effects of cholesterol on the miscibility of synthetic glucosamine diesters in lipid bilayers and the entrapment of superoxide dismutase into the positively charged liposomes Miyajima, K., H. Komatsu, et al. (1993), Chem Pharm Bull (Tokyo) 41(11): 1889-94. Abstract: Methyl-D-glucosamine-3,6-dilauroyl, dimyristoyl, dipalmitoyl or distearoyl esters were synthesized as positively charged lipids. They were incorporated into phosphatidylcholine liposomal membranes and the entrapment of superoxide dismutase (SOD) into the liposomes was attempted. The efficiency of the SOD-entrapment into the positively charged multilamellar vesicles (MLVs), comprising egg yolk phosphatidylcholine and synthetic glucosamine diesters, was enhanced by the addition of cholesterol to the membranes. A differential scanning calorimetric study showed that the miscibility (solubility) of glucosamine diesters in phosphatidylcholine-bilayers increased on the addition of cholesterol to the membranes. Cholesterol assisted in the mixing of phosphatidylcholines with positively charged glucosamine diesters and increased the positive charges on the liposomal membranes. This was confirmed by incremental increases in the zeta-potential of liposomal membranes with an increase in the cholesterol content. Entrapment of SOD thus became more efficient due to the enhanced electrostatic attraction between the positively charged membranes and the negatively charged SOD, and/or the electrostatic repulsive interactions between positively charged membranes; the latter interactions induced a thickening of the water layer in MLVs. |
| Effects of cholesterol on the phenotype of rabbit bile duct fibroblasts Chen, B. Y., J. G. Wei, et al. (2003), World J Gastroenterol 9(2): 351-5. Abstract: AIM: To investigate how cholesterol (Ch) can affect the phenotype of bile duct fibroblasts of New Zealand rabbits. METHODS: 16 rabbits were divided randomly into two groups: the control group and the experiment group. The rabbits in experiment group were fed with hypercholesterol diet for 8 weeks. Bile duct was dissociated from rabbits and prepared for transmission electron microscopy. The purified bile duct fibroblasts were cultured and divided randomly into three groups: control group, Ch middle concentration group (0.6 g/L), Ch high concentration group (1.2 g/L). After incubated for 72 h, the fibroblasts were made into specimens for transmission electron microscopy. The expression of alpha-actin in bile duct fibroblasts was measured by means of laser scanning confocal microscopy. RESULTS: With the transmission electron microscopy, the normal bile duct fibroblasts were shuttle-shaped, and there were abundant rough endoplasmic reticulums (RER), but few mitochondria or microfilaments in cytoplasm. This is the typical phenotype of fibroblasts. Bile duct fibroblasts of hypercholesterolemic rabbits were observed. by the transmission electron microscopy Rough endoplasmic reticulums were significantly reduced, with a lot of microfilament bundles or stress fibers appeared in cytoplasm, especially under plasma membrane. Dense bodies were scattered within these bundles. Macula densas and discontinuous sarcolemma were found under plasma membrane. It suggested that the bile duct fibroblasts of hypercholesterolemic rabbits presented the phenotype of smooth muscle cell. The cultured bile duct fibroblasts also had typical phenotype of fibroblasts. After stimulated by middle concentration cholesterol (0.6 g/L) for 72 h, there appeared lots of microfilaments in cytoplasm, but without dense body, macula densa and discontinuous sarcolemma. Observed with confocal microscopy, there were many regular bundles of microfilaments in fibroblasts treated with middle concentration ch (0.6 g/L) and the expression of alpha-actin was significantly increased. The average fluorescence value of middle concentration group was 1 628+/-189 (P<0.01 vs control group). Microfilaments and the expression of alpha-actin were greatly decreased in fibroblasts of high concentration group (1.2 g/L). The average fluorescence value of high concentration group was 1 427+/-153 (P<0.05 vs middle concentration group). There were a lower expression of alpha-actin and few microfilaments in bile duct fibroblasts of control group with an average fluorescence value of 1 224+/-138. CONCLUSION: Cholesterol can make bile duct fibroblasts have the phenotypic characteristics of smooth muscle cell both in vitro and in vivo and this effect is more significant in vivo. The effect is probably associated with some other factors besides cholesterol. |
| Effects of cholesterol on the structural transitions induced by diacylglycerol in phosphatidylcholine and phosphatidylethanolamine bilayer systems Coorssen, J. R. and R. P. Rand (1990), Biochem Cell Biol 68(1): 65-9. Abstract: The transient membrane lipid diacylglycerol (DG) is known to modify and destabilize phospholipid bilayers and can lead to the formation of nonbilayer structures. Since cholesterol forms a major fraction of many plasma membranes, we have investigated how it modifies the structural effects of DG on bilayers of egg phosphatidylcholine (PC) and egg phosphatidylethanolamine (PE). We view these systems as modelling the behaviour of local, DG-containing sites in membranes. Using X-ray diffraction, we have characterized the lamellar (L alpha) and inverse hexagonal (HII) structures that these ternary lipid mixtures form in excess aqueous solution. As the DG level increases, the lipid progresses from a single L alpha structure to a mixture of L alpha and HII, and then to a pure HII structure. This allows determination of the DG levels at which the HII transition begins, which we interpret as those levels that destabilize bilayers. In both PC and PE bilayers, the presence of 30 mol% cholesterol reduces the amounts of DG required to destabilize the bilayer structure. The destabilization can be translated into the number of neighbouring lipid molecules that a DG molecule perturbs, and of bilayer areas that it affects. The data show that the presence of cholesterol greatly enhances the perturbing effects of DG. We examine the possible role of DG in enzyme activation and membrane fusion. |
| Effects of cholesterol on transmembrane water diffusion in human erythrocytes measured using pulsed field gradient NMR Waldeck, A. R., M. H. Nouri-Sorkhabi, et al. (1995), Biophys Chem 55(3): 197-208. Abstract: The effect of cholesterol on the diffusional permeability of water in suspensions of human erythrocytes was studied by means of pulsed field gradient NMR, which unlike the relaxation NMR method avoids the use of Mn2+ ions. The analysis allows the internal and external diffusion coefficients, as well as the lifetime characterizing the rate of exchange between the two regions, to be extracted from the data. The cholesterol content of the erythrocyte membranes was altered by incubating the cells with sonicated dispersions of cholesterol/dipalmitoyl phosphatidylcholine at 310 K. It was shown that decreasing the molar ratio of cholesterol to phospholipid (C/P ratio) of the membrane, from a mean value of 0.92 for normal cells (controls) to a value of 0.46, had little effect on the intracellular mean residence lifetime and the diffusional permeability. Enriching the cholesterol content of the membrane, however, had a marked effect on the exchange lifetime and the diffusional permeability. At a C/P ratio of approximately 1.5 the rate of transport was reduced approximately 3.5-fold. A further increase of the cholesterol content, to a C/P ratio of approximately 1.9, resulted in an enhancement of the rate of transport back to a normal (control) value, which was characterized by a lifetime of 8-9 ms. The combined inhibition of the water permeability by cholesterol and pCMBS for cells with C/P ratios of 1.44 and 1.54, and by pCMBS alone for cells with a control C/P ratio resulted in the same value for Pd within experimental error. |
| Effects of cholesterol on viability and (n - 6) fatty acid metabolism in cultured human monocyte-like cells (U937) Howie, A., Y. S. Huang, et al. (1992), Biochem Cell Biol 70(8): 643-9. Abstract: Effects of supplementation of growth-promoting cholesterol on metabolism of the cytotoxic (n - 6) polyunsaturated fatty acids in cultured human monocyte-like cells (U937) have been examined. U937 cells were incubated in 5% delipidated fetal bovine serum containing 0 or 38.7 microM cholesterol. The rate of uptake and the distribution of metabolites of (n - 6) fatty acids (such as 18:2(n - 6), 18:3(n - 6), and 20:3(n - 6), and 20:4(n - 6)) were examined by adding radiolabelled fatty acid at a level of 1 microgram/mL (3.3 microM for 20-carbon fatty acids and 3.6 microM for 18-carbon-fatty acids). For assessing the cytotoxicity, (n - 6) fatty acids were added to medium at a concentration of 5 micrograms/mL (16.4 microM for 20-carbon fatty acids and 17.9 microM for 18-carbon fatty acids). Cholesterol supplementation suppressed the uptake of all (n - 6) fatty acids and reduced the cytotoxic effects of 18:2(n - 6), 20:3(n - 6), and 20:4(n - 6), but not 18:3(n - 6). In addition, cholesterol supplementation increased peroxide production and metabolism of (n - 6) fatty acids in U937 cells. Thus, the differential suppressive effect of cholesterol on the cytotoxicity of different fatty acids could not be attributed to an inhibitory effect on fatty acid delta 6- and delta 5-desaturation, or to an antioxidant effect on peroxide formation. |
| Effects of cholesterol- or 7-ketocholesterol-containing liposomes on colony-forming ability of cultured cells Khokhlov, A. N., L. Prokhorov, et al. (1991), FEBS Lett 290(1-2): 171-2. Abstract: Experiments with cultured Chinese hamster cells showed that incubation of the cells with (phosphatidylcholine + cholesterol + 7-ketocholesterol)-containing liposomes (4:3:1 by weight) during two hours led to a decrease in the colony-forming ability of cells down to zero, while (phosphatidylcholine + cholesterol)-containing liposomes (1:1 by weight) reduce this parameter by 90%. Furthermore, the cholesterol-containing liposomes (without 7-ketocholesterol) induce a decrease in the number of the maximal-site colonies accompanied by the corresponding increase in the number of the middle-size colonies. |
| Effects of cholesterol oxidase on cultured vascular smooth muscle cells Liu, K. Z., T. G. Maddaford, et al. (1991), Mol Cell Biochem 108(1): 39-48. Abstract: Cholesterol oxidase (3 beta-hydroxy-steroid oxidase) catalyzes the oxidation of cholesterol to 4-cholesten-3 one and other oxidized cholesterol derivatives. The purpose of the present study was to investigate its effects on cultured vascular smooth muscle cells. Cultured rabbit aortic smooth muscle cells were morphologically altered after exposure to cholesterol oxidase in the presence of culture medium containing 10% fetal calf serum. If fetal calf serum was absent, cells were unaffected by the treatment. The extent of morphological change of the smooth muscle cells was dependent upon the time of exposure to the enzyme and the concentration of cholesterol oxidase employed. After moderate treatment with cholesterol oxidase, cells excluded trypan blue. Further, a specific mitochondrial marker DASPMI (dimethyl aminostyryl-methyl-pyridiniumiodine) which was used as a fluorescent index of cell viability, revealed that cell viability was unchanged after moderate cholesterol oxidase treatment. Nile red, a hydrophobic probe which selectively stains intracellular lipid droplets, was applied to detect the cellular lipid content after treatment with cholesterol oxidase. Cellular nile red fluorescence intensity increased linearly with the time and concentration of cholesterol oxidase treatment. These results demonstrate that cholesterol oxidase alters lipid deposition in the cell and changes cell morphology. The primary site of action of cholesterol oxidase appears to be independent of the cell membrane itself and instead is dependent upon the lipid content in the surrounding culture media. These changes occur prior to the cytotoxic effects of extensive oxidation. Because oxidized cholesterol may play an important role in the pathogenesis of atherosclerosis, our results have implications for intracellular accumulation of lipids in smooth muscle cells during the atherosclerotic lesion. |
| Effects of cholesterol reduction on BP response to mental stress in patients with high cholesterol Sung, B. H., J. L. Izzo, Jr., et al. (1997), Am J Hypertens 10(6): 592-9. Abstract: Impaired endothelium-dependent vascular relaxation has been reported in patients with high cholesterol (HC), but the systemic effects of elevated cholesterol on blood pressure (BP) and BP reactivity to stress have not been studied. We examined the BP response to a standard mental arithmetic test (MAT) in 37 healthy, normotensive HC subjects and 33 normal cholesterol controls (NC). Both groups had similar age, body mass index, and gender distribution. HC had slightly higher systolic BP at baseline (122 v 118 mm Hg, P <.05) than NC and systolic BP response during MAT was significantly higher in HC compared to NC (18 +/- 8 v 10 +/- 5 mm Hg, P <.05). Maximal changes in systolic BP were significantly correlated with cholesterol (R = 0.41, P <.001), whereas heart rate and diastolic BP changes were unrelated to serum cholesterol. To confirm that BP reactivity was dependent on cholesterol, MAT was repeated after treatment with 20 mg/day of lovastatin, a hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, for 6 weeks using a cross-over design in 26 HC subjects. Lovastatin significantly altered lipid profiles (-26% total cholesterol, +8% HDL, -34% LDL). A small decrease in systolic BP at baseline (-3 mm Hg, P = NS) and significantly lower systolic BP (-8 mm Hg, P <.05) during MAT was observed after the treatment with lovastatin. In conclusion, patients with high cholesterol had an exaggerated systolic BP response to MAT. Decreased BP reactivity during HMG-CoA reductase inhibitor therapy suggests that lowering cholesterol may have a role in the overall control of BP. |
| Effects of cholesterol reduction on the properties of arterial walls Struijker Boudier, H. A. (1997), Rev Port Cardiol 16(7-8): 643-4. |
| Effects of cholesterol side-chain groups and adrenodoxin binding on the vibrational modes of carbon monoxide bound to cytochrome P-450scc: implications of the productive and nonproductive substrate bindings Tsubaki, M., S. Yoshikawa, et al. (1992), Biochemistry 31(37): 8991-9. Abstract: Effects of the bindings of cholesterol and its hydroxylated analogues on the Fe-CO stretching and the C-O stretching vibrations of cytochrome P-450scc-CO complex were examined by resonance Raman and FT-IR spectroscopies to reveal the spatial relationship between the steroid side-chain groups and the heme-bound C-O moiety at the active center. These C-O and Fe-CO vibrations exhibited considerable variations depending on the steroids used; however, analyses on the nu Fe-CO vs nu C-O plot for cytochrome P-450scc indicated the absence of the negative correlation between these two vibrations, which is common among various Fe(2+)-porphyrin-CO complexes having imidazole ligands. Rather, we noticed the existence of two groups depending on substrates, the one exhibiting C-O infrared absorption bands in the region from 1930 to 1940 cm-1 and higher enzymatic turnover numbers in the reconstituted enzymatic systems and the other exhibiting C-O infrared absorption bands in the region above 1945 cm-1 and lower enzymatic turnover numbers. Thus, the former substrate group is likely to be fitted into the substrate binding site in the efficient "productive substrate binding" structure, whereas the latter group may be bound to the enzyme in the structure not suitable for the efficient enzymatic reaction ("nonproductive substrate binding" conformation).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Effects of cholesterol supplementation on antioxidant enzyme activities in rat hepatic tissues: possible implications of hepatic paraoxonase in atherogenesis Durak, I., H. Ozbek, et al. (2004), Nutr Metab Cardiovasc Dis 14(4): 211-4. Abstract: BACKGROUND AND AIM: The effects of cholesterol supplementation on antioxidant enzyme activities were investigated hepatic tissue taken from Sprague Dawley rats. METHODS AND REULTS: The study involved 14 male Sprague Dawley rats: seven fed a normal laboratory diet and seven a normal diet plus cholesterol (3.6 g/kg/day) for three months, during which blood samples were obtained to measure serum cholesterol levels. At the end of the 3-month period, the livers were surgically removed in order to measure antioxidant enzyme activities (superoxide dismutase, catalase, glutathione peroxidase and paraoxonase-1). At the end of the study period, serum total cholesterol and HDL-cholesterol levels were significantly higher in the cholesterol-fed group than the control group. There were no significant between-group differences in hepatic superoxide dismutase, catalase and glutathione peroxidase activities, but there was a significant decrease in hepatic paraoxonase-1 activity in the cholesterol-fed group. CONCLUSIONS: Cholesterol supplementation significantly decreases paraoxonase-1 activity in rat liver tissue without changing the activities of other antioxidant enzymes. These results suggest that cholesterol significantly suppresses hepatic paraoxonase-1 synthesis. It seems that the decreased paraoxinase-1 activity in the plasma HDL-fraction of atherosclerotic patients is associated with suppressed liver synthesis. A reduction in paraoxonase-1 activity may therefore lead to the more intensive exposure of LDL to oxidant attacks. |
| Effects of cholesterol uptake from high-density lipoprotein on bile secretion and 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity in perfused rat liver Bravo, E., R. Rivabene, et al. (1993), Metabolism 42(5): 609-14. Abstract: Small aliquots of rat high-density lipoproteins (HDL) (388 +/- 67 nmol lipoprotein cholesterol) were labeled with 14Ccholesterol and administered as a bolus to perfused rat livers. Bile and perfusate samples were collected for 2 hours at 30-minute intervals. After perfusion, both the microsomes and lipid extracts were prepared from the livers. Lipid composition was examined in both liver and microsomes, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was evaluated in microsomes. Basal values of bile flow, lipid composition, and enzyme activity were evaluated using livers in which perfusion was discontinued before injecting the lipoprotein. In some experiments, the effect of perfusion per se was assessed by infusing saline instead of lipoprotein. After 10 minutes of lipoprotein perfusion, 50% of cholesterol administered was taken up by the perfused liver. During infusion, transient but significant increases in both bile flow and bile steroid secretion were observed. Cholesterol administration, even if rapid, represented less than 0.4% of total liver cholesterol content. However, this was enough to significantly increase the cholesterol to phospholipid (CH/PL) molar ratio in liver microsomes and at the same time decrease HMG-CoA reductase activity. In conclusion, the main response of the perfused liver to HDL cholesterol infusion is a reduced activity of the rate-limiting enzyme in cholesterol biosynthesis, due to the shift in the microsomal CH/PL molar ratio. A small proportion of the infused cholesterol enters bile as cholesterol and bile salts. |
| Effects of cholesterol-lowering treatments on oxidative modification of plasma intermediate density lipoprotein plus low density lipoprotein fraction in Type 2 diabetic patients Harada, N., A. Kashiwagi, et al. (1999), Diabetes Res Clin Pract 43(2): 111-20. Abstract: To investigate the normalization of enhanced oxidative modification of the lipoprotein such as increased lysophosphatidylcholine (LPC) and lipid hydroperoxide (LPO) contents in diabetic subjects, we studied the effect of cholesterol-lowering treatment on those parameters in 24 hypercholesterolemic Type 2 diabetic patients. Those patients were randomly assigned to two treatment groups, such as 12 patients treated with pravastatin 10 mg daily and 12 patients treated with probucol 500 mg daily for 8 weeks. Characteristics of the patients including age, gender, body mass index (BMI), smoking habit, modality of diabetic treatment and the glycemic control state were comparable between the two groups. LPC content in the lipoprotein fractions obtained from 24 patients with Type 2 diabetes mellitus was significantly higher than that of non-diabetic control subjects. The abnormality was improved to the control level after a significant improvement of serum cholesterol levels following 8 week-treatments with either probucol or pravastatin without any change in glycemic control (P < 0.025). Furthermore, increased LPO content in the lipoprotein fraction in those diabetics was also significantly (P < 0.0025) improved by the probucol treatment and tended to be improved by pravastatin treatment (P = 0.06). LPC contents in the lipoprotein fraction was positively correlated with LPO contents before cholesterol-lowering treatments (r = 0.41, P < 0.05). These results indicate that cholesterol-lowering treatments effectively reduce oxidative modification of the lipoprotein fraction containing intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) in hypercholesterolemic Type 2 diabetic patients. |
| Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions Collins, R., J. Armitage, et al. (2004), Lancet 363(9411): 757-67. Abstract: BACKGROUND: Lower blood cholesterol concentrations have consistently been found to be strongly associated with lower risks of coronary disease but not with lower risks of stroke. Despite this observation, previous randomised trials had indicated that cholesterol-lowering statin therapy reduces the risk of stroke, but large-scale prospective confirmation has been needed. METHODS: 3280 adults with cerebrovascular disease, and an additional 17256 with other occlusive arterial disease or diabetes, were randomly allocated 40 mg simvastatin daily or matching placebo. Subgroup analyses were prespecified of first "major vascular event" (ie, non-fatal myocardial infarction or coronary death, stroke of any type, or any revascularisation procedure) in prior disease subcategories. Subsidiary outcomes included any stroke, and stroke sub-type. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, "intention-to-treat"), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period. FINDINGS: Overall, there was a highly significant 25% (95% CI 15-34) proportional reduction in the first event rate for stroke (444 4.3% simvastatin vs 585 5.7% placebo; p<0.0001), reflecting a definite 28% (19-37) reduction in presumed ischaemic strokes (p<0.0001) and no apparent difference in strokes attributed to haemorrhage (51 0.5% vs 53 0.5%; rate ratio 0.95 0.65-1.40; p=0.8). In addition, simvastatin reduced the numbers having transient cerebral ischaemic attacks alone (2.0% vs 2.4%; p=0.02) or requiring carotid endarterectomy or angioplasty (0.4% vs 0.8%; p=0.0003). The reduction in stroke was not significant during the first year, but was already significant (p=0.0004) by the end of the second year. Among patients with pre-existing cerebrovascular disease there was no apparent reduction in the stroke rate, but there was a highly significant 20% (8-29) reduction in the rate of any major vascular event (406 24.7% vs 488 29.8%; p=0.001). The proportional reductions in stroke were about one-quarter in each of the other subcategories of participant studied, including: those with coronary disease or diabetes; those aged under or over 70 years at entry; and those presenting with different levels of blood pressure or lipids (even when the pretreatment LDL cholesterol was below 3.0 mmol/L 116 mg/dL). INTERPRETATION: Much larger numbers of people in the present study suffered a stroke than in any previous cholesterol-lowering trial. The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events but also of ischaemic strokes, with no apparent effect on cerebral haemorrhage, even among individuals who do not have high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of ischaemic strokes by about one-quarter and so, after making allowance for non-compliance in the trial, actual use of this regimen would probably reduce the stroke rate by about a third. HPS also provides definitive evidence that statin therapy is beneficial for people with pre-existing cerebrovascular disease, even if they do not already have manifest coronary disease. |
| Effects of cholestyramine on hepatic cholesterol 7alpha-hydroxylase and serum 7alpha-hydroxycholesterol in the hamster Kuroki, S., T. Naito, et al. (1999), Lipids 34(8): 817-23. Abstract: Cholestyramine increases activities of hepatic cholesterol 7alpha-hydroxylase and serum levels of 7alpha-hydroxycholesterol. To examine if serum 7alpha-hydroxycholesterol levels parallel with enzyme activity, 0, 0.5, 1, 2, 4, and 10% of cholestyramine was administered to female golden Syrian hamsters for 28 d in the dose-dependent study, and 2% cholestyramine for 0, 1, 3, 7, 14, 21, and 28 d in the time-dependent study. In the dose-dependent study, hepatic and serum cholesterol levels were significantly decreased dose-dependently when more than 0.5% of cholestyramine was fed for 28 d. Cholestyramine increased the cholesterol 7alpha-hydroxylase activity in a dose-dependent manner, while the serum 7alpha-hydroxycholesterol level was essentially unchanged. No correlation was found between the serum level and the hepatic enzyme activity. In the time-dependent study, hepatic and serum cholesterol levels markedly decreased when 2% cholestyramine was fed for longer than 3 d. The serum triglyceride level increased significantly for the first 7 d and then decreased. Cholesterol 7alpha-hydroxylase activity increased significantly as early as day 1, reached maximum activity level on day 7, and then kept the significantly high values until day 28. The serum 7alpha-hydroxycholesterol level significantly increased for the first 7 d and decreased to the pretreatment level thereafter. 7Alpha-hydroxycholesterol levels significantly correlated with serum cholesterol and triglyceride levels. We conclude that the serum 7alpha-hydroxycholesterol level does not always reflect the activity of hepatic cholesterol 7alpha-hydroxylase, when cholesterol metabolism is severely disturbed by cholestyramine. |
| Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers. A randomized, controlled trial Roeback, J. R., Jr., K. M. Hla, et al. (1991), Ann Intern Med 115(12): 917-24. Abstract: OBJECTIVE: To determine the efficacy of glucose tolerance factor (GTF)-chromium for increasing serum levels of high-density lipoprotein (HDL) cholesterol in patients taking beta-blockers. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Mixed primary and referral-based outpatient clinic at a university-affiliated VA Medical Center. PATIENTS: Referred sample of 72 men receiving beta-blockers, mainly for hypertension. Sixty-three patients (88%) completed the study. INTERVENTIONS: Current medications, including beta-blockers, were continued. During the 8-week treatment phase, patients in the chromium group received a total daily dose of 600 micrograms of biologically active chromium divided into three equal doses; control patients received a placebo of identical appearance and taste. MEASUREMENTS: Serum levels of total cholesterol and HDL cholesterol were measured. MAIN RESULTS: Mean baseline levels of HDL and total cholesterol (+/- SD) were 0.93 +/- 0.28 mmol/L and 6.0 +/- 1.0 mmol/L (36 +/- 11.1 mg/dL and 232 +/- 38.5 mg/dL), respectively. The difference between groups in adjusted mean change in HDL cholesterol levels, accounting for baseline HDL cholesterol levels, age, weight change, and baseline total cholesterol levels, was 0.15 mmol/L (5.8 mg/dL) (P = 0.01) with a 95% Cl showing that the treatment effect was greater than +0.04 mmol/L (+1.4 mg/dL). Mean total cholesterol, triglycerides and body weight did not change significantly during treatment for either group. Compliance as measured by pill count was 85%, and few side effects were reported. Two months after the end of treatment, the between-group difference in adjusted mean change from baseline to end of post-treatment follow-up was -0.003 mmol/L (-0.1 mg/dL). CONCLUSION: Two months of chromium supplementation resulted in a clinically useful increase in HDL cholesterol levels in men taking beta-blockers. |