| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of low density lipoprotein of varying composition on cholesterol levels in human monocyte-derived macrophages McBrinn, S. P., A. H. Johnson, et al. (1994), Biochem Soc Trans 22(1): 36S. |
| Effects of low dose oral contraceptives on serum total cholesterol, TAG, HDL-C & LDL-C levels in contraceptive users Nessa, A., S. A. Latif, et al. (2005), Mymensingh Med J 14(1): 26-8. Abstract: This study was done to appraise the effects of low-dose oral contraceptives (OC(s)) containing synthetic estrogen ethinyl estradiol and synthetic progestin levonorgestrel on serum total cholesterol, TAG, HDL-C and LDL-C levels. Ninety young women within reproductive age group were picked for this study. Sixty women using low-dose oral contraceptives served as experimental group and thirty age matched hormonal contraceptive non-users were selected for control group. Experimental group was again subdivided into OCP users for last one-year group, three-year groups and five-year group. The results showed that there were no significant differences on most of the study parameters between users and non-users women. But there was a significant accession of serum triacylglycerol only in OCP user groups. The results hint that low-dose oral contraceptives regimens partly impaired the lipid metabolism. So, the safeness of low-dose OCP used in National Population Control Program is further inspired. The value of studied parameters for serial longer continuation of OCP uses need to be renegotiated. |
| Effects of low doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol levels in patients with hypercholesterolemia Branchi, A., A. M. Fiorenza, et al. (2001), Clin Ther 23(6): 851-7. Abstract: BACKGROUND: Simvastatin 40 to 80 mg/d has been found to increase high-density lipoprotein cholesterol (HDL-C) levels significantly more than atorvastatin at equipotent doses (ie, 20-80 mg/d). Data on the effects of lower doses of the 2 drugs on HDL-C levels are conflicting. OBJECTIVE: The purpose of this study was to investigate the effects of simvastatin 20 mg/d and atorvastatin 10 mg/d on HDL-C levels in patients with hypercholesterolemia. METHODS: Patients with primary hypercholesterolemia (total cholesterol TC >250 mg/dL) who were not taking any lipid-lowering agents and who were following a low-fat diet were randomized to receive 1 of 2 treatments: simvastatin 20 mg/d or atorvastatin 10 mg/d. Serum TC, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and HDL-C levels were measured using standard methods after 2 months of therapy. In a secondary analysis, lipids and lipoprotein cholesterol were measured after 1 year in patients who continued treatment. RESULTS: Of the 240 patients enrolled (108 men and 132 women; age range, 23-77 years, mean SEM 56.7 0.69), 235 completed the study. After 2 months of therapy, TC, LDL-C, and serum TG levels decreased significantly versus baseline in both groups (P < 0.001), with no significant differences between treatment groups. HDL-C levels increased by 9.0% (P < 0.001 vs baseline) in the simvastatin group and by 4.3% (P < 0.02) in the atorvastatin group. The difference between the 2 groups in the percentage increase in HDL-C was statistically significant (P < 0.05). In 113 patients who continued treatment, HDL-C levels at 1 year were still significantly higher than baseline levels in the simvastatin group (6.3%, P = 0.034), but not in the atorvastatin group (2.8%, P = 0.587). CONCLUSIONS: The findings from this study suggest that the HDL-C-increasing effect of simvastatin 20 mg is significantly greater than that of atorvastatin 10 mg. Since increasing HDL-C levels is thought to lower the risk for atherosclerosis and coronary heart disease, these results warrant further investigation. |
| Effects of low-dose pravastatin sodium on plasma cholesterol levels and aortic atherosclerosis of heterozygous WHHL rabbits fed a low cholesterol (0.03%) enriched diet for one year Harsch, M., J. H. Braesen, et al. (1997), Atherosclerosis 128(2): 139-47. Abstract: The aim of this study was to evaluate the cholesterol-lowering and antiatherosclerotic effect of the HMG-CoA reductase inhibitor pravastatin sodium at a dosage comparable to human therapy. Twelve heterozygous WHHL rabbits (13 months old) were fed 100 g per day of a low cholesterol (0.03%) enriched diet for 12 months. Six of these animals also received pravastatin sodium at a daily dose of 1 mg/kg body weight (verum group). In the verum group, total plasma cholesterol levels were lower by 47%(P < 0.05) and relative aortic plaque volume (% ratio of total plaque volume to the aortic lumen) was reduced by 78% (P < 0.05), when compared to the control group. Plaque composition was analysed at 30 cross-sectional levels of the entire aortic wall using a grid window. Compared to the control group, the plaque type, in terms of architecture and composition, was altered as follows: lesions in the verum group had no confluent atheromatous cores and showed a pattern of a diffuse mixture of the main plaque components with a decreased relative content of necrosis (-44%) and an increased relative content of smooth muscle cells (+19%), whereas the relative content of macrophage-derived foam cells and collagen were nearly unaffected. Furthermore, a similar plaque volume and type was observed in animals with comparable cholesterol profiles. There was no histologic evidence for structurally damaging effects of pravastatin sodium on the arterial wall. We conclude that pravastatin sodium reduces total plasma cholesterol levels in this animal model, thereby leading to smaller plaques and a different plaque type. |
| Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group MacMahon, S., N. Sharpe, et al. (1998), Circulation 97(18): 1784-90. Abstract: BACKGROUND: Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis and lower the risk of coronary heart disease events. However, there has been uncertainty about the effects of cholesterol lowering in patients with average or below-average cholesterol levels. METHODS AND RESULTS: In this study, 522 patients with a history of myocardial infarction or unstable angina and with baseline levels of total cholesterol between 4 and 7 mmol/L (mean, 5.7 mmol/L) were randomized to treatment with a low fat diet plus pravastatin (40 mg daily) or to a low fat diet plus placebo. Treatment with pravastatin reduced the levels of total cholesterol by 19%, LDL cholesterol by 27%, apolipoprotein B by 19%, and triglycerides by 13% (all 2P<.0001) and increased apolipoprotein A1 and HDL cholesterol levels by 4% (both 2P<.0005), in comparison with placebo. Carotid atherosclerosis was assessed from B-mode ultrasound measurements of the common carotid artery. After 4 years, mean carotid wall thickness had increased by 0.048 mm (SE=0.01) in the placebo group and declined by 0.014 mm in the pravastatin-treated group (SE=0.01) (2P for difference <.0001). The effect of treatment on wall thickness was similar in three groups classified by tertiles of total cholesterol at baseline, with mean levels of 4.8, 5.7, and 6.6 mmol/L, respectively (2P for interaction >.8). CONCLUSIONS: Treatment with pravastatin reduced the development of carotid atherosclerosis among patients with coronary heart disease and a wide range of pretreatment cholesterol levels. Treatment with this agent prevented any detectable increase in carotid wall thickening over 4 years of follow-up. |
| Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a) Maher, V. M., B. G. Brown, et al. (1995), Jama 274(22): 1771-4. Abstract: OBJECTIVE--To determine if lowering elevated low-density lipoprotein cholesterol (LDL-C) levels offsets the adverse effect of raised lipoprotein(a) (Lpa) levels on coronary artery disease (CAC) in men. DESIGN--Randomized, double-blind, placebo-controlled trial of lipid lowering for CAD. SETTING--Post hoc analysis of the Familial Atherosclerosis Treatment Study. PARTICIPANTS--A total of 146 men aged 62 years or younger with CAD and apolipoprotein B levels of at least 125 mg/dL. INTERVENTION--Patients received a Step II Diet and lovastatin (40 mg daily) plus colestipol (30 g daily), niacin (4 g daily) plus colestipol, or placebo (plus colestipol if LDL-C > 90th percentile) for 2.5 years. They were grouped by their LDL-C responses: "minimal" if LDL-C decreased by 10% or less from baseline (mean SD change, +6% 13%) and "substantial" if LDL-C decreased more than 10% (mean SD change, -40% 16%). MAIN OUTCOME MEASURE--Impact of lowering elevated LDL-C on the cardiac event rate (death, myocardial infarction, and revascularization for refractory ischemia) and CAD change associated with elevated Lp(a). RESULTS--In multivariate analyses, the best correlate of baseline CAD severity was Lp(a) (r = 0.30; P <.001). For 36 patients with minimal LDL-C reduction, CAD progression correlated only with in-treatment Lp(a) levels (r = 0.45; P <.01), but for 84 patients with substantial LDL-C reduction, disease regressed and its change correlated with in-treatment LDL-C (r = 0.24; P <.05) but not with Lp(a) (r = -0.05). Lipoprotein(a) levels were not significantly altered in either group. For 40 patients with Lp(a) at the 90th percentile or higher, events were frequent (39%) if reduction of LDL-C was minimal, but were few (9%) if reduction was substantial (relative risk, 0.23; 95% confidence interval, 0.06 to 0.99). CONCLUSIONS--In men with CAD and elevated LDL-C, Lp(a) levels were dominant correlates of baseline disease severity, its progression, and event rate over 2.5 years. However, with substantial LDL-C reductions, persistent elevations of Lp(a) were no longer atherogenic or clinically threatening. This provides a possible direction for treatment in such patients with elevated Lp(a) and LDL-C. |
| Effects of low-fat milk and fermented low-fat milk on cholesterol absorption and excretion in ileostomy subjects Andersson, H., I. Bosaeus, et al. (1995), Eur J Clin Nutr 49(4): 274-81. Abstract: OBJECTIVE: To study small bowel cholesterol absorption and sterol excretion in order to explain possible serum cholesterol-lowering mechanisms of low-fat milk products. DESIGN: Two 24-h sterol balance studies with 1 litre of low-fat milk or one litre of fermented milk, in random order, added to a controlled diet. 3HCholesterol absorption was measured during each period. The results were compared to those on two 24-h periods with isocaloric amounts of lemonade given to the same basic diet, before and after the study. One litre of the two milk products was also consumed in addition to their normal diets in a cross-over design of 3 weeks and with run-in and run-out periods of 2 weeks each with 1000 ml of lemonade preceding the balance studies: SETTING: Outpatient clinic, where the subjects were eating their meals during the day and ileostomy bags collected. SUBJECTS: Nine ileostomy subjects, who have earlier participated in similar studies, volunteered for the study. All subjects completed the study. RESULTS: Cholesterol absorption was highest (66%) in the lemonade period, intermediate in the low-fat milk period (61%) and lowest in the fermented low-fat period (55%) (P < 0.05 for differences). Net cholesterol excretion (excretion minus intake) and calculated endogenous cholesterol excretion were significantly (P < 0.05 for differences) higher in the low-fat milk period than in the lemonade period and the fermented low-fat milk period. No significant change in serum cholesterol was, however, seen after 3 weeks on each milk regimen. CONCLUSION: Assimilation of cholesterol by microorganisms could possibly explain the reduced uptake of cholesterol with fermented milk. The mechanism behind the increased endogenous cholesterol excretion, induced by low-fat milk, is unclear. |
| Effects of low-fat stanol ester enriched margarines on concentrations of serum carotenoids in subjects with elevated serum cholesterol concentrations Hallikainen, M. A., E. S. Sarkkinen, et al. (1999), Eur J Clin Nutr 53(12): 966-9. Abstract: OBJECTIVE: To investigate the effects of low-fat stanol ester margarines on concentrations of serum carotenoids. DESIGN: A randomized parallel double-blind study design consisting of a 4-week run-in (high-fat diet) and an 8-week experimental (low-fat, low-cholesterol diet) period. During the experimental diet period subjects consumed low-fat wood stanol ester (WSEM), vegetable oil stanol ester (VOSEM) or control (no stanol esters) margarine daily. The daily mean total stanol intake was 2.31 and 2.16 g in the WSEM and VOSEM groups, respectively. SETTING: Outpatient clinical trial with free-living subjects. SUBJECTS: Altogether, 60 hypercholesterolaemic subjects were selected for the study out of 91 originally screened. The study was completed by 55 subjects. MAIN OUTCOMES MEASURES: Serum alpha- and beta-carotene and lycopene determined by the HPLC. RESULTS: Serum alpha-carotene concentration did not change significantly in either of the experimental groups, whereas beta-carotene concentration decreased significantly in the WSEM and VOSEM groups (P<0.01), and the change differed significantly (P<0.05 and P <0.01, respectively) from that of the control group. Decrease in alpha+beta-carotene concentration was significantly greater (P <0.05) in both experimental groups than in the control group. However, the change in alpha-, beta- or alpha+beta-carotene/total cholesterol ratio did not differ significantly among the groups. No significant changes were found in serum lycopene or lycopene/total cholesterol ratio in both experimental groups. CONCLUSIONS: Low-fat stanol ester margarines appeared to have little effect on serum concentrations of alpha-, beta- or alpha + beta-carotene, or lycopene. SPONSORSHIP: Grant to the University of Kuopio by Raisio Benecol Ltd, Raisio, Finland. |
| Effects of low-intensity aerobic training on the high-density lipoprotein cholesterol concentration in healthy elderly subjects Sunami, Y., M. Motoyama, et al. (1999), Metabolism 48(8): 984-8. Abstract: The concentration of high-density lipoprotein cholesterol (HDL-C) is inversely correlated with the risk of coronary heart disease. The effects of low-intensity aerobic training on serum HDL-C and other lipoprotein concentrations were examined in healthy elderly subjects. The subjects were randomly assigned to two groups matched for sex, age, height, and weight. The training group (n = 20, 10 men and 10 women aged 67 +/- 4 years) participated in a supervised physical exercise regimen using a bicycle ergometer at an intensity of 50% estimated maximal oxygen consumption (VO2max) for 60 minutes two to four times per week for 5 months. In contrast, the control group (n = 20, 10 men and 10 women aged 68 +/- 4 years) did not perform any particular physical training. The training protocol resulted in significant increases in the VO2max (P <.05), HDL-C, HDL2-C, and HDL2-C/HDL3-C ratio (P <.01). The change in HDL2-C (r =.57, P <.01) and HDL2-C/HDL3-C (r =.63, P <.01) was positively associated with an increase in the total exercise duration per week. In addition, the total weekly exercise duration also showed a significant positive relationship with HDL-C (r =.75, P <.01), HDL2-C (r =.81, P <.01), and HDL2-C/HDL3-C (r =.71, P <.01) after the training period. The changes in body weight and the VO2max were not significantly correlated with any lipid parameters. Low-intensity aerobic training may improve the profile of HDL-C and its subfractions in healthy elderly subjects. Also, the total exercise duration may be an important factor for improving HDL-C and HDL2-C in elderly subjects. |
| Effects of lutein and cholesterol on alkyl chain bending in lipid bilayers: a pulse electron spin resonance spin labeling study Yin, J. J. and W. K. Subczynski (1996), Biophys J 71(2): 832-9. Abstract: A short pulse saturation recovery electron spin resonance technique has been used to study the effects of polar carotenoid-lutein and cholesterol on interactions of 14N:15N stearic acid spin-label pairs in fluid-phase phosphatidylcholine (PC) membranes. Bimolecular collisions for pairs consisting of various combinations of 14N-16-, 14N-10-, 14N-7-, or 14N-5-doxylstearate and 15N-16-doxylstearate in dimyristoyl-PC (DMPC) or egg yolk PC (EYPC) membranes were measured at 27 degrees C. In the absence and presence of lutein or cholesterol for both lipid systems, the collision rates were ordered as 16:5 < 16:7 < 16:10 < 16:16. For all spin-label pairs studied, interaction frequencies were greater in DMPC than in EYPC. Polar carotenoid-lutein reduces the collision frequency for all spin-label pairs, whereas cholesterol reduces the collision frequency for 16:5 and 16:7 pairs and increases the collision frequency in the membrane center for 16:10 and 16:16 pairs. The presence of unsaturated alkyl chains greatly reduces the effect of lutein but magnifies the effect of cholesterol in the membrane center. The observed differences in the effects of these modifiers on alkyl chain bending result from differences in the structure of cholesterol and polar carotenoid and from their different localization within the lipid bilayer membrane. These studies further confirm the occurrence of vertical fluctuations of alkyl chain ends toward the bilayer surface. |
| Effects of LY295427, a low-density lipoprotein (LDL) receptor up-regulator, on LDL receptor gene transcription and cholesterol metabolism in normal and hypercholesterolemic hamsters Bensch, W. R., R. A. Gadski, et al. (1999), J Pharmacol Exp Ther 289(1): 85-92. Abstract: The action of LY295427 (3alpha,4alpha, 5alpha)-4-(2-propenylcholestan-3-ol), a compound that derepresses low-density lipoprotein receptor (LDL-R) expression in a cell-based model, was examined in hamsters. It was found that the compound does not have an effect in normal chow-fed hamsters, in which LDL-R levels are not repressed, but exerts a marked hypocholesterolemic effect (>70% decrease) in cholesterol-coconut oil-fed hamsters, in which LDL-R is repressed. In this model, there is a dose-response for cholesterol lowering with an approximate ED50 value of 40 mg/kg/day and an inverse relationship between serum cholesterol and serum LY295427 levels. LDL-R mRNA is increased (2-fold) and liver cholesterol ester content is decreased (>90%). Unlike the 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor lovastatin, the decreased serum cholesterol is confined to the non-high-density lipoprotein fraction. Furthermore, LY295427 does not affect cholesterol biosynthesis, and it does not have a significant effect on cholesterol absorption. These data suggest that LY295427 acts in the hypercholesterolemic hamster by derepressing LDL-R transcription, thereby enhancing cholesterol clearance from the blood. The results with LY295427 suggest that compounds that act to increase LDL-R may represent a novel approach in the pharmacotherapy for hypercholesterolemia. |
| Effects of manipulation of dietary cholesterol on the function of the thoracic aorta from New Zealand white rabbits Dowell, F. J., C. A. Hamilton, et al. (1996), J Cardiovasc Pharmacol 27(2): 235-9. Abstract: Animal studies, while generally showing loss of endothelium-dependent responses after an elevation in plasma cholesterol, have provided conflicting reports with regard to recovery of function after normalisation of cholesterol level. Therefore, we assessed changes in vascular function after a period of hypercholesterolaemia and the subsequent effect of normalisation of cholesterol levels. Contractile responses to phenylephrine (PE) and endothelium-dependent relaxation in response to carbachol were examined in thoracic aorta from New Zealand White rabbits (NZW) fed a 0.3% cholesterol diet for 20 weeks, from NZW fed a 0.3% cholesterol diet for 20 weeks, followed by standard diet for 20 more weeks, and from their respective age-matched controls. Cholesterol levels were increased in rabbits receiving the 0.3% cholesterol diet (12.7 +/- 3.2 mM; 0.5 +/- 0.1 mM control) and returned to normal when standard diet was reintroduced (0.8 +/- 2.0 mM). Contractile responses were not affected by the period of hypercholesterolaemia. Carbachol-induced relaxation of a submaximal PE contraction was impaired after the period of hypercholesterolaemia (Emax 69 +/- 9%; 95 +/- 3% age-matched (control); the effect was reversed after reintroduction of standard diet (Emax 79 +/- 6%; 82 +/- 2% age-matched control). Our results demonstrate that endothelium-dependent relaxation is impaired after a long-term 0.3% cholesterol diet. Furthermore, after reintroduction of a normal diet, there is no further impairment of endothelium-dependent relaxation and endothelium function improves. |
| Effects of manufactured soluble dietary fiber from Quercus mongolica on hepatic HMG-CoA reductase and lipoprotein lipase activities in epididymal adipose tissue of rats fed high cholesterol diets Chai, Y. M., B. K. Lim, et al. (2003), J Med Food 6(4): 329-36. Abstract: This study investigated the effect of a manufactured soluble dietary fiber on lipid metabolism in rats fed high cholesterol diets. Soluble dietary fiber was prepared from wood chips of oak (Quercus mongolica). Male Sprague-Dawley rats weighing 100 +/- 10 g were randomly assigned to either a normal diet or five high cholesterol diets containing 1% cholesterol and different fiber supplements. The high cholesterol groups were subdivided into fiber-free diet (FF), 5% pectin (5P), 10% pectin (10P), 5% manufactured soluble dietary fiber (5QM), and 10% manufactured soluble dietary fiber (10QM) groups. Total serum cholesterol concentrations in all soluble dietary fiber-supplemented groups were lower than in the FF group. The high-density lipoprotein-cholesterol concentration in the FF group was significantly lower, compared with the normal group, but was increased in groups supplemented with soluble dietary fiber. Low-density lipoprotein-cholesterol levels and the atherogenic index had the same tendency as total cholesterol concentration. Compared with the FF group, in the 5P, 5QM, 10P, and 10QM groups hepatic triglyceride concentrations were 12%, 16%, 20%, and 24% lower, respectively, and hepatic cholesterol concentrations were 48%, 52%, 52%, and 58% lower, respectively. Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in the soluble fiber groups was significantly higher than in the FF groups, but lower than the normal group. When hepatic tissue was observed under a light microscope, the FF group had completely formed lipomas in the hepatic tissue, which led to fat deposits and then a fatty liver. The size and number of lipomas were lower in the soluble dietary fiber-fed groups, as compared with the group not fed dietary fiber. In conclusion, improvements in lipid metabolism were observed as a result of the manufactured soluble dietary fiber from the oak chips, and were similar to that seen for pectin. The preparation method for the soluble dietary fiber from oak chips successfully produced a functional soluble fiber. |
| Effects of mass transfer and reaction kinetics on serum cholesterol depletion rates of free and immobilized Pseudomonas pictorum Garofalo, F. A. and T. M. Chang (1991), Appl Biochem Biotechnol 27(1): 75-91. Abstract: Pseudomonas pictorum in free or immobilized form can deplete serum cholesterol. The reaction kinetics control the global rate of cholesterol depletion during the initial part of free P. pictorum fermentation. Then, mass transfer takes control of the global rate. In this part of the fermentation, the global rate is first order with respect to the cholesterol concentration. The halftime was 330 min. The global rate is zero order with respect to the bacterial concentration. The activation energy was 83 kJ/mol. These results are consistent with the aqueous cholesterol diffusion model. The open pore agar microcapsule experimental effective diffusivity for lipoproteins at 37 degrees C was 6.7 x 10(-11) m2/s. Mass transfer across the microcapsule was not the limiting factor for the global rate. |
| Effects of membrane cholesterol manipulation on excitation-contraction coupling in skeletal muscle of the toad Launikonis, B. S. and D. G. Stephenson (2001), J Physiol 534(Pt 1): 71-85. Abstract: 1. Single mechanically skinned fibres and intact bundles of fibres from the twitch region of the iliofibularis muscle of cane toads were used to investigate the effects of membrane cholesterol manipulation on excitation-contraction (E-C) coupling. The cholesterol content of membranes was manipulated with methyl-beta-cyclodextrin (MbetaCD). 2. In mechanically skinned fibres, depletion of membrane cholesterol with MbetaCD caused a dose- and time-dependent decrease in transverse tubular (t)-system depolarization-induced force responses (TSDIFRs). TSDIFRs were completely abolished within 2 min in the presence of 10 mM MbetaCD but were not affected after 2 min in the presence of a 10 mM MbetaCD-1 mM cholesterol complex. There was a very steep dependence between the change in TSDIFRs and the MbetaCD: cholesterol ratio at 10 mM MbetaCD, indicating that the inhibitory effect of MbetaCD was due to membrane cholesterol depletion and not to a pharmacological effect of the agent. Tetanic responses in bundles of intact fibres were abolished after 3-4 h in the presence of 10 mM MbetaCD. 3. The duration of TSDIFRs increased markedly soon (< 2 min) after application of 10 mM MbetaCD and 10 mM MbetaCD-cholesterol complexes, but the Ca(2+) activation properties of the contractile apparatus were minimally affected by 10 mM MbetaCD. The Ca(2+) handling abilities of the sarcoplasmic reticulum appeared to be modified after 10 min exposure to 10 mM MbetaCD. 4. Confocal laser scanning microscopy revealed that the integrity of the t-system was not compromised by either intra- or extracellular application of 10 mM MbetaCD and that a large Ca(2+) gradient was maintained across the t-system. 5. Membrane cholesterol depletion caused rapid depolarization of the polarized t-system as shown independently by spontaneous TSDIFRs induced by MbetaCD and by changes in the fluorescence intensity of an anionic potentiometric dye (DiBAC(4)(3)) in the presence of MbetaCD. This rapid depolarization of the t-system by cholesterol depletion was not prevented by blocking the Na(+) channels with TTX (10 microM) or the L-type Ca(2+) channels with Co(2+) (5 mM). 6. The results demonstrate that cholesterol is important for maintaining the functional integrity of the t-system and sarcoplasmic reticulum, probably by having specific effects on different membrane proteins that may be directly or indirectly involved in E-C coupling. |
| Effects of membrane cholesterol on the sensitivity of the GABA(A) receptor to GABA in acutely dissociated rat hippocampal neurones Sooksawate, T. and M. A. Simmonds (2001), Neuropharmacology 40(2): 178-84. Abstract: The effects of membrane cholesterol on the GABA(A) receptor were investigated in acutely dissociated rat hippocampal neurones, using the whole-cell patch clamp technique. Neuronal cholesterol was manipulated within the range 56-250% control by incubation with methyl-beta-cyclodextrin for depletion and a complex of cholesterol and methyl-beta-cyclodextrin for enrichment. Manipulation over a narrower range was achieved with cholesterol + phosphatidylcholine liposomes. A complex of epicholesterol and methyl-beta-cyclodextrin was used to insert epicholesterol. Cholesterol enrichment reduced the potency of GABA, as did cholesterol depletion, with increases in EC(50) of up to 4-fold. Cholesterol enrichment reduced the potency of the competitive antagonist bicuculline but did not affect that of the non-competitive antagonist picrotoxinin. Cholesterol depletion did not affect the potencies of either antagonist. Epicholesterol substituted functionally for cholesterol with respect to the effects of enrichment. In cholesterol-depleted neurones, however, only incubation with cholesterol was able to restore GABA potency to normal. These results suggest a specific requirement for cholesterol at control levels to maintain optimal GABA potency, which may involve specific binding of cholesterol to the GABA(A) receptor. The reduction in GABA potency by enrichment with cholesterol or epicholesterol is more likely to be due to reduced plasma membrane fluidity. |
| Effects of membrane lipid composition on the kinetics of cholesterol exchange between lipoproteins and different species of red blood cells Gold, J. C. and M. C. Phillips (1990), Biochim Biophys Acta 1027(1): 85-92. Abstract: To better understand the effects of plasma membrane structure on the kinetics of cellular cholesterol efflux to extracellular lipoprotein particles, the influence of plasma membrane sphingomyelin (SM) on the kinetics of cholesterol exchange was examined in both a model membrane system comprised of egg SM/egg phosphatidylcholine (PC) unilamellar vesicles and in various types of mammalian red blood cells (RBC) containing differing levels of SM. The kinetics and mechanism of the bidirectional flux of unesterified cholesterol (FC) between RBC and lipoproteins were established by using human RBC (labeled with 14CFC) incubated with varying concentrations of human 3HFC high-density lipoprotein (HDL3) or 3HFC low-density lipoprotein (LDL). A maximal rate constant for FC efflux was obtained when the lipoprotein FC was in excess (6-fold and 15-fold, for HDL3 and LDL, respectively) of RBC FC; under this condition, the rate-limiting step is desorption of cholesterol molecules from the RBC membrane into the extracellular aqueous phase. At 37 degrees C, the halftime (t1/2) for efflux was 4.6 +/- 0.6 h for HDL3 and 6.2 +/- 0.2 h for LDL; FC efflux exhibited first-order kinetics and the RBC FC comprised a single kinetic pool. To investigate the effect of different membrane SM/PC ratios on the rate of FC desorption from the plasma membrane, the kinetics of cholesterol efflux from bovine RBC (5:1, w/w ratio of SM/PC), human RBC (1:1 ratio), rabbit RBC (0.6:1 ratio) and rat RBC (0.3:1 ratio) were compared. With excess HDL3 present, bovine, rabbit, and rat RBC exhibited t1/2 of 5.5 +/- 0.8, 4.0 +/- 0.2, and 3.7 +/- 0.6 h, respectively, for cholesterol efflux. Changing the ratio from 0.3:1 to 3:1 in egg SM/egg PC small unilamellar vesicles increased the t1/2 for cholesterol efflux at 45 degrees C from 1.1 to 6.9 h. The results described in this paper suggest that increasing membrane SM content raises the t1/2 for cholesterol exchange in both the RBC plasma membrane and in simple mixed SM/PC bilayers. However, the influence of SM is less in the natural plasma membrane, perhaps because of modulating factors such as membrane proteins and the presence of a complex phospholipid mixture. |
| Effects of membrane lipids and -proteins and cytoskeletal proteins on the kinetics of cholesterol exchange between high density lipoprotein and human red blood cells, ghosts and microvesicles Gold, J. C. and M. C. Phillips (1992), Biochim Biophys Acta 1111(1): 103-10. Abstract: To better understand the effects of plasma membrane lipids and proteins and the cytoskeleton on the kinetics of cellular cholesterol efflux, the effects of (1), selectively depleting either sphingomyelin (SM) or phosphatidylcholine (PC); (2), cross-linking the cytoskeleton, and (3), removing certain cytoskeletal and integral membrane proteins on radiolabelled cholesterol efflux from red blood cells (RBC) have been studied. When RBC were treated with either phospholipase A2 or sphingomyelinase C to hydrolyze either 30-40% of the PC or 40-50% of the SM, respectively, the halftimes (t1/2) for cholesterol efflux to excess HDL3 were not significantly altered, with the values being 4.4 +/- 0.8 h or 3.7 +/- 0.4 h, respectively, compared to 4.6 +/- 0.6 h for control RBC. To investigate the effects of the cytoskeleton on the rate of free cholesterol (FC) desorption from the plasma membrane, the cytoskeletal proteins were cross-linked by either heat-treatment or exposure to diamide and cholesterol efflux from ghosts of these cells was measured. Cross-linking the cytoskeletal proteins by diamide treatment resulted in no significant change in t1/2 for treated (3.6 +/- 0.6 h) compared to control (4.2 +/- 0.4 h) ghosts: this suggests that the cytoskeleton does not play a large role in modulating cholesterol efflux. To investigate the effects of membrane proteins on cholesterol efflux, RBC microvesicles, containing mainly band 3 and 4 proteins and little of the cytoskeletal proteins, such as spectrin (bands 1,2) or actin (band 5), were obtained by incubation with the ionophore A23187. With excess HDL3 present, microvesicles exhibited a t1/2 of 4.2 +/- 1.9 h (compared to the t1/2 of 4.2 +/- 0.4 h for control ghosts). The results described in this paper suggest that neither changing the SM/PC ratio in the membrane nor cross-linking the cytoskeletal proteins nor removing the cytoskeleton changes the t1/2 for cholesterol efflux to excess HDL3. Presumably, the cholesterol-phospholipid interactions are insensitive to these perturbations in membrane structure. |
| Effects of menopause on trends of serum cholesterol, blood pressure, and body mass index Akahoshi, M., M. Soda, et al. (1996), Circulation 94(1): 61-6. Abstract: BACKGROUND: To elucidate the impact of menopause on coronary risk factors, we determined the trends of serum cholesterol (mg/dL), blood pressure (BP, mm Hg), and body mass index (BMI, kg/m2) and investigated whether menopause affects these trends in women in Nagasaki, Japan. METHODS AND RESULTS: Trends of cholesterol, systolic BP (SBP), and BMI from 9 years before menopause through 9 years after menopause in 579 women with natural menopause (ranging in age from 40.2+/-3.1 to 57.9+/-3.1 years; age at menopause, 49.4+/-3.0 years) and 134 women with surgical menopause (hysterectomy with or without bilateral oophorectomy; ranging in age from 34.9+/-4.5 to 51.7+/-5.1 years; age at menopause, 42.9+/-5.0 years) and those in 579 and 134 age- and time-matched male subjects (ranging in age from 40.1+/-3.1 to 57.8+/-3.2 years and from 35.2+/-4.5 to 51.6+/-5.0 years, respectively) in Nagasaki were determined by rearrangement of the data from 1958 to 1989 with time of menopause as the datum line. Although cholesterol tended to increase with age in both sexes, it increased significantly in women from 3 years before natural menopause to 1 year after natural menopause and from 1 year before surgical menopause to 1 year after surgical menopause. SBP and BMI did not exhibit a significant increase in relation to natural or surgical menopause. In male subjects, no significant increase of cholesterol, SBP, or BMI was observed at the age corresponding to natural or surgical menopause. CONCLUSIONS: Natural menopause and surgical menopause exert an effect only on cholesterol, and an increase in cholesterol precedes natural menopause by 3 years and occurs at the time of surgical menopause. |
| Effects of mepanipyrim on intracellular trafficking: a comparative study on its effects on exocytic and endocytic trafficking of proteins, sphingolipids, and cholesterol Miura, I., M. Muroi, et al. (1996), Biosci Biotechnol Biochem 60(10): 1690-7. Abstract: Mepanipyrim, N-(4-methyl-6-prop-1-ynylpyrimidin-2-yl)aniline, diminished the cell surface expression of envelope glycoproteins of Newcastle disease and vesicular stomatitis viruses at concentrations where their synthesis was not profoundly affected. Intoxication by diphtheria toxin and ricin and recycling of transferrin were not affected even when cells were treated with mepanipyrim for 2 h before the addition of these probes, indicating that mepanipyrim does not act on the endocytic and recycling pathways of these proteins. Metabolic conversion of C6-NBD-ceramide to sphingomyelin and its back-exchange to the medium was also not affected, but synthesis and back-exchange of C6-NBD glucosylceramide were greatly influenced, and an accumulation of LDL-derived, unesterified cholesterol was induced by the drug. These results are discussed relating to the site(s) of action of mepanipyrim. |