| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of sphingomyelin and phosphatidylcholine degradation on cyclodextrin-mediated cholesterol efflux in cultured fibroblasts Ohvo, H., C. Olsio, et al. (1997), Biochim Biophys Acta 1349(2): 131-41. Abstract: The hydrolysis of plasma membrane sphingomyelin is known to dramatically alter cellular cholesterol homeostasis in different ways, whereas the degradation of plasma membrane phosphatidylcholine has much less or no effects on cell cholesterol homeostasis Porn, Ares, Slotte, J. Lipid Res. 34 (1993) 1385-1392. In this study, we used an efficient extracellular cholesterol acceptor (cyclodextrin) and determined the extent of cholesterol efflux from cultured fibroblasts in which plasma membrane sphingomyelin or phosphatidylcholine was degraded. Treatment of cells with sphingomyelinase reduced the cell sphingomyelin content by about 76% (about 13 nmol SM degraded), and dramatically increased the desorption of 3Hcholesterol from the plasma membrane to 2-hydroxypropyl-beta-cyclodextrin. The corresponding hydrolysis of cell surface phosphatidylcholine (about 12% reduction of the cellular phosphatidylcholine content, corresponding to about 12 nmol degraded PC) had almost no effect on cell 3Hcholesterol efflux. The stimulatory effect of sphingomyelin degradation on cell 3Hcholesterol efflux was reversible, since rates of 3Hcholesterol efflux dropped back to control levels when cells (in this case baby hamster kidney cells) were allowed to restore their sphingomyelin content by re-synthesis in the absence of sphingomyelinase. The findings of this study clearly demonstrate that plasma membrane sphingomyelin markedly affected the rate of cholesterol transfer between cells and an extracellular acceptor (i.e., cyclodextrin), whereas the effect of phosphatidylcholine on cholesterol efflux was much smaller. |
| Effects of sphingomyelin degradation on cholesterol mobilization and efflux to high-density lipoproteins in cultured fibroblasts Slotte, J. P., J. Tenhunen, et al. (1990), Biochim Biophys Acta 1025(2): 152-6. Abstract: The hydrolysis of sphingomyelin from cellular plasma membranes imposes many consequences on cellular cholesterol homeostasis by causing a rapid and dramatic redistribution of plasma membrane cholesterol within the cells (Slotte, J.P. and Bierman, E.L. (1988) Biochem. J. 250, 653-658). The objective of this study was to examine the effects of an extracellular cholesterol acceptor on the directions of the sphingomyelinase-induced cholesterol flow in cultured fibroblasts. We have used HDL3 as a physiological acceptor for cholesterol, and measured the effects of sphingomyelin hydrolysis on efflux and endogenous esterification of cellular 3Hcholesterol. Treatment of cells with sphingomyelinase did induce a dramatically increased esterification of plasma-membrane-derived 3Hcholesterol. The presence of HDL3 in the medium (100 micrograms/ml) did not prevent or reduce the extent of the sphingomyelinase-induced cellular esterification of 3Hcholesterol. Degradation of cellular sphingomyelin (75% hydrolysis) also did not enhance the rate of 3Hcholesterol efflux from the plasma membranes to HDL3. In addition, we also observed that the degradation of sphingomyelin in the HDL3 particles (complete degradation) did not change the apparent rate of 3Hcholesterol transfer from HDL3 to the cells. These findings together indicate that hydrolysis of sphingomyelin did not markedly affect the rates of cholesterol surface transfer between HDL3 and cells. By whatever mechanism cholesterol is forced to be translocated from the plasma membranes subsequent to the degradation of sphingomyelin, it appears that the sterol flow is specifically directed towards the interior of the cells. |
| Effects of spinach leaf protein concentrate on the serum cholesterol and amino acid concentrations in rats fed a cholesterol-free diet Satoh, A., M. Hitomi, et al. (1995), J Nutr Sci Vitaminol (Tokyo) 41(5): 563-73. Abstract: The effects of spinach leaf protein concentrate (SPPC) on serum and liver lipid concentrations and on serum free amino acid concentrations were examined in rats fed a cholesterol-free diet containing 2 and 10% fats. The serum total cholesterol, triacylglycerol and phospholipid concentrations in the rats fed an SPPC diet containing 2% corn oil were significantly lower than those of the rats fed a corresponding casein diet. When 10% corn oil or lard was used, the serum cholesterol-lowering effect of the SPPC became insignificant, but the serum and liver triacylglycerol concentrations were kept at significantly lower levels. Both the amounts of fecal neutral steroids and bile acids were significantly higher in the rats fed the SPPC than those of the casein-fed rats. The concentrations of serum threonine, serine, glutamine, glycine, cystine, and isoleucine were significantly higher in the rats fed the SPPC diet containing 2% corn oil compared with those of the control rats, but when the dietary fat was raised to 10%, only glycine showed a higher serum concentration. These results indicate that the SPPC has a stronger cholesterol-lowering effect at a lower dietary fat level, 2%, and the activity is partly due to the inhibition of intestinal absorption of cholesterol and bile acid, and partly due to an increase in the concentration of some of the serum amino acids. |
| Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol Liao, J. K. (2005), Am J Cardiol 96(5A): 24F-33F. Abstract: Statins are potent inhibitors of cholesterol biosynthesis and exert beneficial effects in the primary and secondary prevention of coronary artery disease. However, the overall benefits observed with statins appear to occur much earlier and to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of the small guanosine triphosphate-binding proteins Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins. |
| Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide Fassbender, K., M. Stroick, et al. (2002), Neurology 59(8): 1257-8. Abstract: Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta. |
| Effects of stent design and serum cholesterol level on the restenosis rate in atherosclerotic rabbits Tominaga, R., H. Harasaki, et al. (1993), Am Heart J 126(5): 1049-58. Abstract: We investigated the effect of serum cholesterol level and stent design on the restenosis rate within the stent after balloon angioplasty and stent implantation using atherosclerotic rabbits. Two types of nickel/titanium stents with gaps (open stent) and without gaps (closed stent) between the wire coils were implanted into the aorta of the rabbits 10 weeks after atherosclerosis had been induced using a standard high cholesterol diet and balloon abrasion. Each rabbit had an open stent and a closed stent implanted into the infrarenal abdominal aorta. Between these two stents a control segment of the aorta was treated with angioplasty alone. The animals were divided into two groups according to the diet protocol as follows: in group I (n = 9) a high cholesterol diet was stopped after stent implantation; in group II (n = 10) a high cholesterol diet was maintained after stent implantation. Digital subtraction angiograms were obtained every 4 weeks for up to 24 weeks and the narrowest diameter of the arterial segments within each stent and in the segment between stents was measured. The diameter narrowing within the closed stent was greater in the high cholesterol group compared with the low cholesterol group: 12 weeks (2.57 +/- 0.09 mm in group I vs 2.14 +/- 0.15 mm in group II, mean +/- S.E., p < 0.05); 16 weeks (2.55 +/- 0.09 mm vs 2.14 +/- 0.12 mm, p < 0.05); 20 weeks (2.59 +/- 0.06 mm vs 1.98 +/- 0.12 mm, p < 0.01); and 24 weeks (2.45 +/- 0.11 mm vs 2.01 +/- 0.11 mm, p < 0.05). No significant differences in the narrowest diameter of the arterial segments were observed between high and low cholesterol groups in the angioplasty alone areas or within the open stents. There was a significant difference in the narrowest diameter between stents with versus those without gaps (at 12, 16, and 20 weeks poststenting in group I and at 4, 8, 12, 16, 20, and 24 weeks in group II). Thus the stent with the least metal is correlated with less stenosis and intimal hyperplasia. From these data we conclude that both stent design and serum cholesterol are important factors for restenosis after stent implantation. |
| Effects of stimulated growth hormone secretion on age-related changes in plasma cholesterol and hepatic low density lipoprotein messenger RNA concentrations Walker, R. F., G. C. Ness, et al. (1994), Mech Ageing Dev 75(3): 215-26. Abstract: Growth hormone (GH) secretion declines during aging. Since GH alters plasma cholesterol (PC) concentrations, it was of interest to determine how GH secretagogues affect age-related hypercholesterolemia. Fischer 344 rats (3 and 14 months old) were co-administered (s.c.) GH releasing hormone (3 micrograms/kg; GHRH) and GH releasing hexapeptide (100 micrograms/kg; GHRP) for 120 consecutive days. Aging was associated with a progressive increase in PC, which was reduced in rats administered GHRH and GHRP compared to those administered vehicle, i.e. changes in PC during the study were 26.5 +/- 1.2 mg/dl vs. 40.1 +/- 0.9 mg/dl (P < 0.05) in the younger rats and 17.6 +/- 2.3 mg/dl vs. 31.6 +/- 5.3 mg/dl (P < 0.05) in the older rats, respectively. The lower concentrations of PC in GH secretagogue-treated older rats were associated with higher mean concentrations of hepatic LDL receptor mRNA (1.27 +/- 0.4 vs. 0.4 +/- 0.1; P < 0.05) but not cholesterol 7-alpha hydroxylase mRNA. Although GH secretagogue treatment was also associated with lower plasma cholesterol in the younger rats, it was not accompanied by quantitative changes in mean group concentrations of hepatic LDL receptor mRNA. Instead, daily administration of GHRH and GHRP in the younger rats correlated with a significant reciprocal relationship (P < 0.05) between PC and hepatic LDL receptor mRNA for individual group members. The results of this study suggest that reduced GH secretion during aging contributes, at least in part, to a progressive increase in plasma cholesterol that can be partially prevented with GH secretagogues. Furthermore, the effects on PC may result from GH-mediated, qualitative and quantitative changes in hepatic LDL receptor mRNA that increase receptor-mediated cholesterol clearance. |
| Effects of subchronic clozapine administration on serum glucose, cholesterol and triglyceride levels, and body weight in male BALB/c mice Cheng, C. Y., C. J. Hong, et al. (2005), Life Sci 76(19): 2269-73. Abstract: Atypical antipsychotics, like clozapine, have fewer extrapyramidal side effects compared with typical antipsychotics, however, such treatment is associated with several adverse metabolic effects such as weight gain, hyperglycemia and hyperlipidemia in patients with schizophrenia. In this study, we investigated the effects of 30-day clozapine treatment on weight change, and serum fasting glucose, cholesterol and triglyceride levels in male BALB/c mice. The results demonstrate that 10.0 mg/kg clozapine group gained significantly less weight but had higher cholesterol compared with controls and the 2.0 mg/kg clozapine group. Our findings indicate the possibility of using mice to study the mechanisms of body weight change and lipid dysregulations induced by clozapine. |
| Effects of submaximal exercise on high-density lipoprotein-cholesterol subfractions Park, D. H. and J. W. Ransone (2003), Int J Sports Med 24(4): 245-51. Abstract: Acute high-density lipoprotein-cholesterol (HDL) changes were determined in 18 healthy college aged-men completing two-counterbalanced running trials at different exercise intensities: trial 1 at 70 % lactate threshold (LT) (372.5 +/- 28.9 kcal); trial 2 at LT intensity (365.9 +/- 75.9 kcal). For each trial, blood samples were collected at pre-exercise (baseline), 15 min post-exercise (15 m PE) and 24 hours post-exercise (24 h). Serum samples were analyzed for HDL/HDL 2 /HDL 3 subfraction, low density lipoprotein (LDL), very low density lipoprotein (VLDL), total cholesterol (TC), free cholesterol (FC), cholesterol ester, and triglycerides (TG). In addition, capillary blood samples were collected for analysis of blood lactate concentrations during incremental test to determine LT. All samples were corrected for plasma volume changes and compared to pre-exercise (baseline). In assessing the lipid and lipoprotein variables, the significant increase in HDL (p < 0.05) at the 24 h was due to the increase in both HDL 2 and HDL 3. The increase in 15 m PE TC at the LT intensity occurred while the decreases in 24 h TG and VLDL concentrations at the LT intensity occurred at different time periods, respectively. These decreases in the concentrations of TG and VLDL were significantly different, contributing to change in 24 h HDL concentration. No significant difference was determined in changes of HDL over time ratios of FC/CE and HDL 2 /HDL 3. Therefore, the significant increase in 24 h HDL at LT intensity was potentially due to increases in both HDL 2 and HDL 3 subfractions even though 24 h FC was increased significantly. Exercise at LT intensity might favourably alter the lipid profile as demonstrated in 24 h HDL concentration in combination with decreases in TG and VLDL at 24 h post-exercise. Consequently, the LT intensity might appear to be the threshold intensity of acute aerobic exercise (expending 350 kcal) necessary to promote a significant increase in HDL. |
| Effects of superoxide dismutase on the acetylcholine-induced relaxation response in cholesterol-fed and streptozotocin-induced diabetic mice Kamata, K., M. Nakajima, et al. (1999), J Smooth Muscle Res 35(2): 33-46. Abstract: High concentration of acetylcholine (ACh) caused a rapid and long lasting relaxation response in age-matched controls, whereas this response was significantly weaker in streptozotocin (STZ)-diabetic and cholesterol fed mice. The levels of basal and ACh-stimulated cyclic GMP in the aorta was also significantly smaller in STZ-diabetic and cholesterol-fed mice. The attenuated relaxation responses to ACh in both STZ-diabetic and cholesterol-fed mice were ameliorated by the chronic administration of cholestyramine. A prior incubation of aortic strips with superoxide dismutase (SOD, 60 U/ml) improved the recovery phase of the relaxation of diabetic aorta after single administration of ACh, whereas SOD had no effects on ACh-induced relaxation of aortic strips from cholesterol fed mice. These results suggest that superoxide anion may be responsible for an impairment of endothelium-dependent relaxation of aorta from STZ induced diabetic mice. It is further suggested that impairment of endothelium-dependent relaxation in STZ-diabetic and cholesterol fed mice may be caused by different mechanisms. |
| Effects of supplemental ascorbic acid on performance, organ weight and plasma cholesterol concentration in broilers treated with propylthiouracil Takahashi, K., Y. Akiba, et al. (1991), Br Poult Sci 32(3): 545-54. Abstract: 1. Four experiments were conducted to determine if dietary ascorbic acid (AA) affects body weight gain, food intake, organ weights, plasma cholesterol concentration, and ascorbic acid concentration in the plasma and liver of growing male broilers treated with an antithyroidal agent, propylthiouracil (PTU). 2. In the first experiment, 15 mg AA was administered daily into the crop of chicks fed on a diet supplemented with or without PTU (500 mg/kg). Administration of AA reduced plasma cholesterol concentrations in the PTU-treated chicks. 3. In the other three experiments, chicks were given the basal diet or an AA-containing (3 g/kg) diet supplemented with or without PTU (250 mg or 500 mg/kg). Feeding AA partly prevented the decreases in body weight gain, gain:food ratio and weights of the bursa of Fabricius and thymus in chicks fed on the 250 mg/kg PTU diet, and also prevented the increase in plasma cholesterol concentrations in chicks fed on the PTU diet. 4. These results suggest that AA improves the performance of chicks with experimentally induced hypothyroidism. |
| Effects of surface charges and cholesterol content on amino acid permeabilities of small unilamellar vesicles Sada, E., S. Katoh, et al. (1990), J Pharm Sci 79(3): 232-5. Abstract: The permeabilities of amino acids through bilayer lipid membranes were determined using small unilamellar vesicles (SUV). Alanine, lysine, arginine, and glutamate show permeabilities on the order of 10(-10)-10(-11) cm/s in the case of SUV prepared from dimyristoylphosphatidylcholine and dicetylphosphate. An increase in the amount of negative charges introduced by dicetylphosphate enhanced the permeability of the positively charged amino acid (i.e., lysine). The permeabilities of net charged amino acids decreased with an increase in cholesterol content, and became less than 10(-12) cm/s with the membrane which consists of equimolar amounts of dimyristoylphosphatidylcholine and cholesterol. |
| Effects of sustained moderate exercise on cholesterol, growth hormone and cortisol blood levels in three age groups of women Cearlock, D. M. and N. A. Nuzzo (2001), Clin Lab Sci 14(2): 108-11. Abstract: OBJECTIVE: The objective of this study was to determine the effects of sustained moderate exercise on cholesterol, cortisol, and growth hormone blood levels in women of three age groups. DESIGN: A four-week exercise program followed by one week of no exercise. The exercise program consisted of 20 minutes of moderate exercise three times a week for four weeks. Venipuncture was performed weekly. SETTING: The exercise and venipunctures took place in a large room with phone access and ample space to move. PARTICIPANTS: A convenience sample of five pre-menopausal (20 to 30 years), 11 peri-menopausal (40 to 50 years), and 9 post-menopausal (60 to 85 years) healthy women participated in the study. MAIN OUTCOME MEASURES: Paired samples t-tests were used to compare changes in cholesterol, growth hormone, and cortisol of individuals from week zero (pre-exercise) to week four (last exercise) to week five (one week post exercise). RESULTS: There were no significant differences between pre-exercise and post-exercise growth hormone levels for post-menopausal women, however, there appeared to be a trend in growth hormone increase over time. There were no significant differences between pre-exercise and post-exercise cholesterol levels for any of the three age groups of women but trends for decreased cholesterol levels were observed in the peri-menopausal and post-menopausal women. Cortisol levels did not appreciably change in response to regular exercise. CONCLUSION: Although this study did not generate definitive data there were trends toward the proposed hypotheses. Future studies may include increasing the number of participants, implementing a longer test period to validate exercise-induced increases in growth hormone and decreases in cholesterol levels, and employing insulin-like growth factor (IGF-1) as an indicator of growth hormone levels. |
| Effects of switching statins on achievement of lipid goals: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study Schuster, H., P. J. Barter, et al. (2004), Am Heart J 147(4): 705-13. Abstract: BACKGROUND: In a multinational trial (4522IL/0081), we assessed the effects of switching to low doses of rosuvastatin from commonly used doses of atorvastatin, simvastatin, and pravastatin on low-density lipoprotein cholesterol (LDL-C) goal achievement in high-risk patients. METHODS: Hypercholesterolemic patients (n = 3140) with coronary heart disease, atherosclerosis, or type 2 diabetes were randomized to open-label rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg, or pravastatin 40 mg for 8 weeks. Patients either remained on these treatments for another 8 weeks or switched treatments from atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg to rosuvastatin 10 mg or from atorvastatin 20 mg to rosuvastatin 10 or 20 mg. The primary efficacy measure was the proportion of patients reaching the Joint European Societies' LDL-C goal (<116 mg/dL) at week 16. For measures of cholesterol goal achievement, treatment arms were compared using logistic-regression analysis. RESULTS: Significant improvement in LDL-C goal achievement was found for patients who switched to rosuvastatin 10 mg, compared with patients who remained on atorvastatin 10 mg (86% vs 80%, P <.05), simvastatin 20 mg (86% vs 72%, P <.0001), and pravastatin 40 mg (88% vs 66%, P <.0001), and between patients switched to rosuvastatin 20 mg and those who remained on atorvastatin 20 mg (90% vs 84%, P <.01). Similar results were found for achievement of the European combined LDL-C and total cholesterol goals and National Cholesterol Education Program Adult Treatment Panel III LDL-C goals. All statins were well tolerated over 16 weeks. CONCLUSIONS: We demonstrated that switching to a more efficacious statin is an effective strategy to improve lipid goal achievement in patients requiring lipid-lowering therapy. |
| Effects of taurine on depletion of erythrocyte membrane Na-K ATPase activity due to ozone exposure or cholesterol enrichment Qi, B., T. Yamagami, et al. (1995), J Nutr Sci Vitaminol (Tokyo) 41(6): 627-34. Abstract: The objective of this study was to investigate the interrelationship between taurine and erythrocyte-membrane Na-K ATPase activity. A comparison was conducted to test whether taurine or uric acid (a water-soluble scavenger of free radicals) prevents or recovers the depletion in membrane ouabain-sensitive Na-K ATPase activity resulting from ozone exposure or cholesterol enrichment of the erythrocyte membrane. A depletion of 44% and 27% in ouabain-sensitive Na-K ATPase activity was respectively caused by ozone exposure and cholesterol enrichment. Taurine as well as uric acid partially prevented the activity loss from ozone exposure. In addition, taurine at high concentrations (from 1.5 to 4.5 mM) restored the depletion of erythrocyte-membrane Na-K ATPase activity due to ozone exposure and prevented the depletion of the enzyme activity due to cholesterol enrichment. In contrast, although the same high concentrations were used, uric acid failed to show either of the above effects. These results suggest that taurine acts (1.5-4.5 mM) polyvalently as not only an antioxidizing agent but also as a membrane stabilizer to maintain the functions of membrane Na-K ATPase, a membrane-bound protein. |
| Effects of taurine on serum cholesterol levels and development of atherosclerosis in spontaneously hyperlipidaemic mice Matsushima, Y., T. Sekine, et al. (2003), Clin Exp Pharmacol Physiol 30(4): 295-9. Abstract: 1. The effects of two naturally occurring substances, namely taurine and catechins, on serum cholesterol levels and on the progression of atherosclerotic lesions were evaluated using spontaneously hyperlipidaemic (SHL) mice as an animal model of atherogenesis. 2. Twelve weeks treatment of SHL mice with taurine (1% in drinking water) significantly elevated serum high-density lipoprotein-cholesterol (HDL-C) levels without affecting levels of low-density lipoprotein- and very low-density lipoprotein-cholesterol. In addition, taurine suppressed the development of atherosclerotic lesions by 29%, as determined by oil red O-stained areas in cross-sections of the aorta. 3. In contrast, 12 weeks treatment with a catechin mixture had no apparent effect on serum cholesterol levels and on the progression of atherosclerosis. 4. Serum levels of thiobarbituric acid-reactive substances, an index of oxidized substances, significantly decreased from 9.6 to 6.7 nmol/mL following taurine treatment. 5. We suggest that retardation of atherosclerosis by taurine in SHL mice may be related to decreases in oxidized substances and increases in serum HDL-C levels. |
| Effects of testosterone on cholesterol levels and fatty acid composition in the rat Cinci, G., R. Pagani, et al. (1993), Life Sci 53(2): 91-7. Abstract: The effects of testosterone treatment on cholesterol levels and its fatty acid components were studied in adult rats. Cholesterol levels increased both in the liver and in the serum of castrated rats. Androgen administration restored the normal values only in the serum. A general decrease in unsaturated and essential fatty acids in cholesterol esters was evident after testosterone administration. In the liver, only the C16:O/C16:1 ratio clearly increased after testosterone administration, which inhibited the delta 9 unsaturation of palmitic acid, but not of stearic acid. In the serum the C16:O/C16:1, C18:O/C18:1, and C18:2/C2O:4 ratios decreased after castration and were restored by testosterone. The results indicate a clear inhibition of delta 9 unsaturation of palmitic and stearic acids, of delta 5 unsaturation and elongation in organs other than the liver. No effect was evident on delta 6 unsaturation. This suggests that fatty acid unsaturations are regulated differently by testosterone in different tissues. For delta 9 unsaturation in the liver, the effect also seems to be substrate-dependent. |
| Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans Harris, W. S., C. A. Dujovne, et al. (1990), Clin Pharmacol Ther 48(2): 189-94. Abstract: A common pharmacologic approach to lowering elevated serum cholesterol levels has been to interfere with intestinal sterol absorption. Inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) should produce this effect. In this study, we examined the effects of CL 277,082, N-(2,4-difluorophenyl)-N-(4-neopentylbenzyl)-N-(n-heptyl)urea, an ACAT inhibitor, on cholesterol metabolism in humans. Eight healthy male volunteers were given a placebo for 14 days, followed by 750 mg/day CL 277,082 for 20 days in a single-blind, crossover design. Subjects were studied in a hospital research unit and were fed strictly controlled diets. Cholesterol absorption was measured by the dual isotope method during the final week of both the placebo and the drug phases. Sterol balance was also assessed during these two periods by measuring cholesterol intake, and fecal neutral and acidic sterol excretion rates. Plasma lipids and lipoproteins were measured at the end of each period. The drug was well tolerated and produced no detectable clinical or laboratory side effects. Cholesterol absorption, sterol excretion rates, and plasma lipoprotein levels were all unaffected by treatment. We conclude that CL 277,082 may not interfere with ACAT activity or cholesterol absorption in humans at the doses given under the conditions tested in this study. |
| Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions Tardif, J. C., J. Gregoire, et al. (2004), Circulation 110(21): 3372-7. Abstract: BACKGROUND: Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis. METHODS AND RESULTS: This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level <125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was approximately 200 mm3, and the least squares mean change at end of treatment was 0.7 mm3 for placebo and 7.7, 4.1, and 4.8 mm3 for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted P=0.17 unadjusted P=0.057, 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (P=NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups (P<0.05 in all groups). CONCLUSIONS: Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol. |
| Effects of the apolipoprotein E polymorphism on uptake and transfer of cell-derived cholesterol in plasma Huang, Y., A. von Eckardstein, et al. (1995), J Clin Invest 96(6): 2693-701. Abstract: The reverse cholesterol transport is initiated by the uptake of cholesterol into minor subfractions of high density lipoproteins (HDL) which contain either apolipoprotein (apo) A-I or apoE as their only apolipoproteins. From these initial acceptors, which are termed prebeta1-LpA-I and gamma-LpE, respectively, cell-derived cholesterol is transferred to LDL via the bulk of HDL termed alpha-LpA-I. In this study we analyzed the effect in plasma of the genetically determined apoE polymorphism on the formation of gamma-LpE, uptake and transfer of cell-derived cholesterol to LDL. Gamma-LpE was immunologically detectable in plasmas of individuals carrying at least one apoE3-allele but not in apoE3-free plasmas. During one minute incubation with 3Hcholesterol-labeled fibroblasts, gamma-LpE of plasmas from apoE3/3 subjects accumulated 7 and 13-fold more radioactivity than the respective fractions in plasmas from apoE2/2- and apoE4/4-subjects, respectively. Totally, 30% less 3Hcholesterol was released into plasmas of apoE2/2 and apoE4/4-individuals as compared with plasmas of apoE3/3-subjects. Moreover, plasmas of apoE3/3 individuals accumulated 50% and 65% more cell-derived 3Hcholesterol in alpha-LpA-I2 than plasmas of apoE4/4 and apoE2/2-subjects, respectively. These results indicate that the apoE-polymorphism is an important determinant of the uptake and transfer of cell-derived cholesterol in plasma. |