| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Effects of mevinolin, an inhibitor of cholesterol synthesis, on the morphology and function of differentiating and differentiated rat adrenocortical cells in primary culture Heikkila, P., A. I. Kahri, et al. (1990), Cell Tissue Res 261(1): 125-32. Abstract: Mevinolin, an inhibitor of cholesterol synthesis, was used to study the effect of endogenous cholesterol synthesis on the morphology and function of differentiating and differentiated fetal rat adrenocortical cells grown in primary culture. Upon adrenocorticotrophic hormone (ACTH) stimulation under conditions in which endogenous cholesterol synthesis was inhibited but exogenous (lipoprotein) cholesterol was available, the cells differentiated normally from glomerulosa-like to fasciculata-like cells; the steroid hormone secretion was maximally induced. Under conditions in which cholesterol synthesis was maximally inhibited by mevinolin and the cells had no access to exogenous cholesterol, the cells did not differentiate into fasciculata-like cells; the ACTH-induced steroid response was highly suppressed under these conditions. The addition of either human low-density lipoprotein (LDL) or high-density lipoprotein (HDL3) to the culture medium restored the ACTH-induced differentiation and steroid secretion. Thus, in the absence of exogenous cholesterol, endogenous cholesterol synthesis was a prerequisite for differentiation. In cultures grown in the presence of exogenous cholesterol and ACTH with mevinolin-inhibited cholesterol synthesis and high steroid output, an increase in cytoplasmic lipids was evident, suggesting upregulation of LDL and HDL receptors. The results also demonstrated that induction of phenotypic differentiation from glomerulosa-like into fasciculata-like cells can proceed in the presence of a cholesterol synthesis inhibitor like mevinolin; this differentiation in the absence of endogenous cholesterol synthesis is accompanied by the appearance of cytoplasmic cholesterol ester droplets, typical of fasciculata cells. |
| Effects of micronized fenofibrate versus atorvastatin in the treatment of dyslipidaemic patients with low plasma HDL-cholesterol levels: a 12-week randomized trial Despres, J. P., I. Lemieux, et al. (2002), J Intern Med 251(6): 490-9. Abstract: BACKGROUND: Studies have suggested that raising low levels of high-density lipoprotein cholesterol (HDL-C) may be an important target for the prevention of coronary heart disease. OBJECTIVE: To compare the ability of micronized fenofibrate and atorvastatin to increase plasma HDL-C levels. DESIGN: Multicentre, randomized open-label study. Settings. The study was conducted in 19 centres across the UK and Canada. SUBJECT: One hundred and eighty-one patients were randomized and the full analysis set included 165 nondiabetic patients with low HDL-C (women <46 mg dL-1, i.e. 1.2 mmol L-1 and men <43 mg dL-1, i.e. 1.1 mmol L-1): 86 patients in the atorvastatin group and 79 patients in the micronized fenofibrate group. Interventions. Micronized fenofibrate (200 mg day-1, 87 patients) or atorvastatin (10 mg day-1, 94 patients) for a period of 12 weeks. Main outcome measures. Percent change in HDL-C levels. RESULT: After 12 weeks of treatment, the mean percent change from baseline in HDL-C was significantly higher in the micronized fenofibrate group (13.3%) compared with the atorvastatin group (5.3%, P=0.0003). The magnitude of such relative change was inversely related to the baseline HDL-C levels only in the micronized fenofibrate group. Furthermore, in the fenofibrate treatment group, 50.9% of the patients (29 of 57 patients) with a baseline HDL-C <40 mg dL-1 achieved a plasma HDL-C level above 40 mg dL-1 after 12 weeks of treatment versus 27.9% of the patients (19 of 68 patients) in the atorvastatin group (P=0.01). CONCLUSIONS: On the basis of (1) the greater impact of fenofibrate than atorvastatin on HDL-C levels and (2) the greater proportion of dyslipidemic patients achieving HDL-C levels above 40 mg dL-1 with fenofibrate than atorvastatin, it is suggested that micronized fenofibrate should be considered as a good therapeutic option to treat dyslipidemic patients with low HDL-C and moderately elevated LDL-C concentrations. |
| Effects of misoprostol on circulating HDL-cholesterol, total cholesterol, triglycerides and their relationship with hepatic microsomal function Godinho, A. F. and M. A. Silva (1995), Pharmacol Toxicol 77(4): 255-8. Abstract: The effects of misoprostol (cytotec, SC29333) on circulating lipoproteins and liver microsomal enzyme activity were studied. Misoprostol increased serum levels of high density lipoprotein-cholesterol and decreased total cholesterol and triglycerides. The high density lipoprotein-cholesterol/total cholesterol ratio increased by 54.8%. In parallel, misoprostol significantly altered enzyme hepatic activity. Liver microsomal cytochromes P450 and b5 were significantly increased in correlation with enhanced liver aminopyrine N-demethylase and antipyrine hydroxylase activities, suggesting a liver induction effect of misoprostol. Other observations such as increased liver weight and glycogen and increased plasma albumin and glucose in rats receiving misoprostol support this evidence. |
| Effects of Momordica charantia powder on serum glucose levels and various lipid parameters in rats fed with cholesterol-free and cholesterol-enriched diets Jayasooriya, A. P., M. Sakono, et al. (2000), J Ethnopharmacol 72(1-2): 331-6. Abstract: The effects of dietary bitter melon (Momordica charantia) freeze-dried powder on serum glucose level and lipid parameters of the serum and liver were studied in rats fed diets supplemented with and without cholesterol. Rats were fed the diets for 14 days containing bitter melon freeze-dried powder at the level of 0.5, 1 and 3% without an added dietary cholesterol (experiment I) and those containing bitter melon at the level of 1% with or without 0.5% cholesterol and 0.15% bile acid (experiment II). No adverse effect of dietary bitter melon powder on growth parameters and relative liver weight were noted. Dietary bitter melon resulted in a consistent decrease in serum glucose levels in rats fed cholesterol-free diets, but not in those fed cholesterol-enriched diets, although no dose-response was noted. Addition of cholesterol to the diets as compared to those without added cholesterol caused hypercholesterolemia and fatty liver. Bitter melon had little effect on serum lipid parameters, except for high density lipoprotein (HDL)-cholesterol; HDL-cholesterol levels tended to decrease by dietary cholesterol, while they were consistently elevated by dietary bitter melon both in the presence and absence of dietary cholesterol, indicating an antiatherogenic activity of bitter melon. In addition, bitter melon exhibited a marked reduction in the hepatic total cholesterol and triglyceride levels both in the presence and absence of dietary cholesterol; the reduction of triglyceride levels in the absence of dietary cholesterol was in a dose-dependent manner. These results suggest that bitter melon can be used as a health food. |
| Effects of monatepil maleate, a new Ca2+ channel antagonist with alpha1-adrenoceptor antagonistic activity, on cholesterol absorption and catabolism in high cholesterol diet-fed rabbits Ikeno, A., T. Sumiya, et al. (1998), Jpn J Pharmacol 78(3): 303-12. Abstract: The mechanism of the prophylactic effect against hyperlipidemia by monatepil maleate was investigated in animal models. Monatepil maleate is an antihypertensive agent with Ca2+-channel antagonistic, alpha1-adrenergic receptor-blocking, and lipid peroxidation inhibitory activity. In high cholesterol diet-fed rabbits, monatepil maleate (30 mg/kg, p.o., once daily for 9 weeks) showed a prophylactic effect against increases in total cholesterol and beta-lipoprotein. Monatepil maleate significantly accelerated the clearance of radioactivity from the blood after intravenous injection of low-density lipoprotein (LDL) labeled with 1alpha,2alpha (n)-3Hcholesterol, increasing biliary excretion of 3H-bile acids without modifying bile acid composition. Furthermore, monatepil maleate tended to inhibit the absorption of orally administered 1alpha,2alpha (n)-3Hcholesterol from the gastrointestinal tract in these rabbits. In Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of hepatic LDL receptor deficiency, monatepil maleate (30 mg/kg, p.o., once daily for 6 months) did not suppress the increase in plasma lipids. These results suggest that the plasma lipid lowering effect of monatepil maleate requires the presence of hepatic LDL receptors. It is also suggested that monatepil maleate improves plasma lipid metabolism through two mechanisms: enhancement of clearance of plasma LDL, which may be mediated by up-regulation of hepatic LDL receptors, and acceleration of conversion of free cholesterol to bile acids in the liver. |
| Effects of naproxen and nabumetone on serum cholesterol levels in patients with osteoarthritis Young, D., C. Peterson, et al. (1995), Clin Ther 17(2): 231-40. Abstract: In a 12-week controlled clinical study of the effects of two nonsteroidal anti-inflammatory drug regimens on serum lipoproteins in patients with osteoarthritis, 54 patients were treated with naproxen, 500 mg twice daily, and 45 patients were treated with nabumetone, 1,000 mg once daily. In patients who received naproxen, the mean levels of total serum cholesterol decreased by 18.3 mg/dL (7.0%) from baseline to 12 weeks, high-density lipoprotein (HDL) cholesterol remained unchanged, and low-density lipoprotein (LDL) cholesterol decreased by 15.4 mg/dL (8.7%). In patients who received nabumetone, mean levels of total serum cholesterol increased 10.4 mg/dL (4.0%), HDL cholesterol remained unchanged, and LDL cholesterol increased 7.2 mg/dL (4.1%). Furthermore, serum triglyceride levels tended to increase in nabumetone-treated patients and decrease in naproxen-treated patients, with a statistically significant (P < 0.05) difference between treatments. The decreases in total cholesterol and LDL cholesterol levels in patients receiving naproxen were statistically significant (P < 0.01). These results confirm previous findings on naproxen's cholesterol-lowering effect. |
| Effects of National Cholesterol Education Program Step 2 diets relatively high or relatively low in fish-derived fatty acids on plasma lipoproteins in middle-aged and elderly subjects Schaefer, E. J., A. H. Lichtenstein, et al. (1996), Am J Clin Nutr 63(2): 234-41. Abstract: The effects of two National Cholesterol Education Program (NCEP) Step 2 diets (< or = 30% of energy as total fat, < 7% of energy as saturated fat, and < 200 mg cholesterol/d), one relatively high and the other relatively low in fish-derived fatty acids, on plasma lipoprotein concentrations and blood pressure were compared in 22 men and women with a mean (+/- SD) age of 63 +/- 10 y. Subjects were placed on a baseline diet similar to the diet currently consumed in the United States (35% of energy as total fat, 14% of energy as saturated fat, 35 mg cholesterol/MJ) for 6 wk and then on either an NCEP Step 2 diet relatively high in fish (Step 2 high-fish, n = 11) or relatively low in fish (Step 2 low-fish, n = 11) for 24 wk. All food and drinks were provided. Compared with baseline values, consumption of both the Step 2 high-fish and the Step 2 low-fish diets under weight-stable conditions was associated with significant decreases in plasma concentrations of total cholesterol (-14% and -19%, respectively), low-density-lipoprotein (LDL) cholesterol (-15% and -20%, respectively), and high-density-lipoprotein (HDL) cholesterol (-11% and -17%, respectively). Postprandial, but not fasting, triacylglycerol concentrations were significantly reduced during consumption of the Step 2 high-fish diet. There were no significant changes in these indexes after consumption of the Step 2 low-fish diet compared with the baseline diet. LDL particle size decreased significantly (-12%) only in subjects on the Step 2 low-fish diet. Both Step 2 diets caused small but significant reductions in diastolic blood pressure. Our results indicate that NCEP Step 2 diets relatively high or relatively low in fish are both effective in significantly reducing total and LDL-cholesterol concentrations without changes in the ratio of total cholesterol to HDL cholesterol under controlled weight-stable conditions in middle-aged and elderly subjects. A beneficial effect on diastolic blood pressure was also observed. |
| Effects of natural and enantiomeric cholesterol on the thermotropic phase behavior and structure of egg sphingomyelin bilayer membranes Mannock, D. A., T. J. McIntosh, et al. (2003), Biophys J 84(2 Pt 1): 1038-46. Abstract: Phospholipids, sphingolipids, and sterols are the major lipid components of the plasma membranes of eukaryotic cells. Because these three lipid classes occur naturally as enantiomerically pure compounds, enantiospecific lipid-lipid and lipid-sterol interactions could in principle occur in the lipid bilayers of eukaryotic plasma membranes. Although previous biophysical studies of phospholipid and phospholipid-sterol model membrane systems have consistently failed to observe such enantiomerically selective interactions, a recent monolayer study of the interactions of natural and enantiomeric cholesterol with egg sphingomyelin has apparently revealed the existence of enantiospecific sterol-sphingolipid interactions. To determine whether enantiospecific sterol-sphingolipid interactions also occur in more biologically relevant lipid-bilayer systems, differential scanning calorimetric, x-ray diffraction, and neutral buoyant-density measurements were utilized to study the effects of natural and enantiomeric cholesterol on the thermotropic phase behavior and structure of egg sphingomyelin bilayers. The calorimetry experiments show that the natural and enantiomeric cholesterol have essentially identical effects on the temperature, enthalpy, and cooperativity of the gel/liquid-crystalline phase transition of egg sphingomyelin bilayers within the limits of experimental error. As well, the x-ray diffraction and neutral buoyancy experiments indicate that bilayers formed from mixtures of natural or enantiomeric cholesterol and egg sphingomyelin have, within experimental uncertainty, the same structure and mass density. We thus conclude that significant enantioselective cholesterol-sphingolipid interactions do not occur in this lipid-bilayer model membrane system. |
| Effects of NB-598, a potent squalene epoxidase inhibitor, on the apical membrane uptake of cholesterol and basolateral membrane secretion of lipids in Caco-2 cells Horie, M., Y. Iwasawa, et al. (1993), Biochem Pharmacol 46(2): 297-305. Abstract: Caco-2 cells grown on membrane filters were used as a model to study the effects of NB-598, an inhibitor of squalene epoxidase, on cholesterol absorption from the intestinal epithelia. NB-598 (10 microM) inhibited the synthesis of sterol and sterol ester from 14Cacetate without affecting the synthesis of other lipids such as phospholipids (PL), free fatty acids (FFA) and triacylglycerol (TG). When labeled lipid was apically loaded as a micellar lipid solution into Caco-2 cell cultures, NB-598 reduced basolaterally secreted radioactivity in cholesterol, cholesterol ester, PL and TG. Furthermore, NB-598 suppressed the basolateral secretion of apolipoprotein (apo) B. When microsomes prepared from control Caco-2 cells were incubated with 10 microM NB-598, acyl CoA:cholesterol acyltransferase (ACAT) activity was inhibited slightly. After incubating Caco-2 cells with 10 microM NB-598, a slight reduction in cellular ACAT activity was also observed. These results suggest that suppression of the secretion of particles containing apo B and reduction of cellular ACAT activity in the intestinal epithelia are part of the mechanism of the cholesterol-lowering effect of NB-598. |
| Effects of nicardipine on lipid peroxidation in rabbits given 2% cholesterol diet Ismail, N. M., K. Jaarin, et al. (1995), Pharmacol Toxicol 77(1): 10-5. Abstract: Nicardipine has been shown to have an anti-atherogenic effect in rabbits given a 2% cholesterol diet. Current evidence suggests that lipid peroxidation plays an important role in atherogenesis. This study examines the effect of nicardipine on lipid peroxidation in rabbits given a 2% cholesterol diet, 8 of these rabbits given nicardipine 0.5 mg/kg twice daily intramuscularly for ten weeks while the remaining untreated 6 were controls. After ten weeks, serum malondialdehyde in the control group was significantly higher compared to their baseline levels (P < 0.05). However, there was no increase in serum malondialdehyde in the nicardipine group after 10 weeks. The area of Sudan IV positive intimal lesions (atherosclerotic plaques) were significantly decreased (P < 0.01) in the treated group compared to the control group. The aortic tissue content of cholesterol and diene conjugates were also decreased in the nicardipine group (P < 0.01). These findings suggest a possible link between nicardipine and lipid peroxidation in mediating its antiatherogenic effects. |
| Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia Wahlberg, G., G. Walldius, et al. (1990), J Intern Med 228(2): 151-7. Abstract: Nicotinic acid was given in a 4-g daily dose for 6 weeks to 41 weight-stable patients of mean age (+/- SD) 52 +/- 9 years, with type IIa, type IIb or type IV hyperlipoproteinaemia (HLP), in order to study its effects on serum cholesterol concentrations of high density lipoprotein (HDL) subfractions HDL2 and HDL3. The triglyceride and cholesterol levels of serum very low density (VLDL) and low density (LDL) lipoproteins decreased during treatment (P less than 0.001). Serum HDL and HDL2 cholesterol levels increased by 37% and 135%, respectively. These changes were positively correlated (r = 0.93; P less than 0.001). There was no significant change in mean serum HDL3 cholesterol concentration. A negative correlation existed between changes in HDL3 and HDL2 cholesterol levels (r = -0.54; P less than 0.001). Multiple stepwise linear regression analyses revealed that the initial HDL3 cholesterol predicted more than 30% of the increase in HDL2 cholesterol. Changes in the concentrations of HDL2 and HDL3 cholesterol after 6 weeks of drug treatment were not related to the type of HLP, neither were these effects of nicotinic acid correlated with changes in VLDL or LDL lipid levels. The concept has previously been proposed, on the basis of in vitro data, that HDL2 is formed from HDL3 particles in the blood. Our results suggest that, in man, this reaction is stimulated in vivo by prolonged nicotinic acid therapy. |
| Effects of nifedipine and Paeonia lactiflora on plasma TXB2 and 6-Keto-PGF1 alpha in cholesterol-fed rabbits Zhang, Y. Z. and X. F. Yan (1990), Zhong Xi Yi Jie He Za Zhi 10(11): 669-71, 645. Abstract: The authors examined the influences of nifedipine and Paeonia lactiflora (PL) on plasma LPO, TXB2 and 6-keto-PGF1 alpha in cholesterol-fed rabbits. In this study, oral administration of nifedipine (15 mg/kg per day) and PL (0.5 g/kg per day) with 2% cholesterol diet for 15 weeks caused 60.75% and 74.24% reduction in the lesion area of aorta respectively. The levels of plasma LPO, TXB2, cholesterol, phospholipid and calcium of the intimalmedia of the aorta in the treated groups were significantly lower than those in the control group, but the level of 6-keto-PGF1 alpha in the treated groups was significantly higher. The durations of TXB2 elevation and 6-keto-PGF1 alpha reduction were delayed. The ratio of TXB2/6-keto-PGF1 alpha tended to balance. The ratio of TXB2/6-keto-PGF1 alpha was significantly positive correlation with the percentage of lesion area of the aorta. It is demonstrated that calcium metabolism plays an important role in thromboxane, prostaglandin, and LPO synthesis. In conclusion, the inhibition of LPO production and the regulation of TXA2-PGI2 balance may be one of the mechanisms of anti-atherogenesis of calcium antagonists and PL. |
| Effects of nitric oxide on cholesterol metabolism in macrophages Shimizu, H., T. Taniguchi, et al. (1997), Atherosclerosis 129(2): 193-8. Abstract: Nitric oxide (NO) is associated with atherogenic process by inhibiting the proliferation of vascular smooth muscle cells, adhesion of monocyte/macrophages, aggregation and adhesion of platelets and oxidation of LDL, but it is not clear whether NO affects cellular cholesterol metabolism or not. We investigated cholesterol metabolism in murine macrophages (J774A.1) by regulating NO production. Incubation with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, had no influence on cellular cholesterol accumulation induced by LDL or acetylated LDL (acetyl-LDL). Lipopolysaccharide (LPS) stimulated NO production in a dose-dependent manner in the presence of LDL or acetyl-LDL but did not change LDL-induced cellular cholesterol accumulation. In the presence of acetyl-LDL, LPS stimulated NO production but significantly inhibited cholesteryl ester accumulation in a dose-dependent manner (37.7% decrease by 100 micrograms/ml of LPS), but LPS simulation did not change free cholesterol content. NG-monomethyl-L-arginine (L-NMMA), inhibitor of NO synthase, suppressed NO production and addition of L-arginine restored NO production, but these regulations did not alter LPS-induced esterified cholesterol reduction. These results suggest that NO generation in atherosclerotic lesions does not influence cholesterol metabolism in macrophages. |
| Effects of non-beta-oxidizable sulfur-substituted fatty acid analogues on synthesis and secretion of triacylglycerol and cholesterol in cultured rat hepatocytes Skorve, J., A. C. Rustan, et al. (1995), Lipids 30(11): 987-94. Abstract: The mechanisms behind the hypolipidemic effect of two sulfur-substituted fatty acid analogues, 3-thiadicarboxylic acid and tetradecylthioacetic acid, have been investigated in cultured hepatocytes. There was a dose-dependent reduction in incorporation of 3H water into triacylglycerol and diacylglycerol when tetradecylthioacetic acid was added to rat hepatocytes cultured in the presence of 200 muM oleic acid. Tetradecylthioacetic acid also increased the oxidation of 14Cpalmitic acid compared to oleic acid, inhibited the incorporation of radiolabeled precursors into diacylglycerol to a greater extent than into triacylglycerol, and reduced the secretion of triacylglycerol more than its synthesis. A stimulation, rather than a reduction, in glycerolipid synthesis and secretion by oxidation of fatty acids and reduces the synthesis and secretion of glycerolipids. 3-Thiadicarboxylic acid reduces the synthesis and secretion of both glycerolipids and cholesterol to approximately the same extent without a concomitant increase in the oxidation of fatty acids. |
| Effects of non-esterified stanols in a liquid emulsion on cholesterol absorption and synthesis in hypercholesterolemic men Gremaud, G., E. Dalan, et al. (2002), Eur J Nutr 41(2): 54-60. Abstract: BACKGROUND Numerous studies have shown that dietary plant sterols (phytosterols and phytostanols) and their esters can decrease cholesterol absorption. However, few researchers have examined the effects of plant sterols on cholesterol absorption and synthesis using stable isotope tracers, instead of relying on endogenous pathway precursors. Further, we have worked with non-esterified lecithin-solubilized stanols as opposed to the more frequently studied esterified sterols and stanols. The vehicle was an oil-in-water liquid emulsion rather than the more common spread vehicle typically employed. AIM OF THE STUDY: To determine the effects of relatively low doses of lecithin-solubilized non-esterified stanols in liquid emulsions on cholesterol absorption and synthesis in mildly hypercholesterolemic subjects. METHODS: In a randomized, double blind crossover design, 12 mildly hypercholesterolemic men received either a free phytostanol supplement (3 g/d in 3 servings) or a control treatment for 3 days. Cholesterol endogenous synthesis rate was determined using the rate of incorporation of deuterium from body water into newly formed cholesterol molecules. Cholesterol absorption at the intestinal level was determined using the dual isotope method using 13C cholesterol injected intravenously and 180 cholesterol given orally. RESULTS: Cholesterol absorption was 55.7 +/- 6.5 % for the control and 33.5 +/- 5.3% for the phytostanol treatment. This massive reduction of the cholesterol absorption did not induce, on average, a difference in cholesterol endogenous synthesis which was measured at 0.074 +/- 0.0015 pool/d for plant sterols and 0.0736 +/- 0.0015 pool/d for controls (p > 0.05). CONCLUSIONS: The results demonstrated that lecithin-solubilized stanols administrated during a short period of time (3 days) in an oil-in-water emulsion can dramatically decrease cholesterol absorption, without a consistent, concomitant increase in synthesis, which is highly suggestive of effective LDL cholesterol lowering. The effects of synthesis should be verified in a longer study with more subjects. |
| Effects of nonpharmacologic therapy with cardiac rehabilitation and exercise training in patients with low levels of high-density lipoprotein cholesterol Lavie, C. J. and R. V. Milani (1996), Am J Cardiol 78(11): 1286-9. Abstract: In a study of 591 consecutive coronary patients, we identified 243 (41%) with low high-density lipoprotein (HDL) cholesterol <35 mg/dl and demonstrated the benefits of vigorous nonpharmacologic therapy with cardiac rehabilitation and exercise training in this subgroup. However, patients with low HDL and "normal" triglycerides have significantly greater improvements in low-density lipoprotein (LDL) cholesterol and LDL/HDL ratio than patients with low HDL cholesterol and hypertriglyceridemia who are more likely to require drug treatment. |
| Effects of novel bile salts on cholesterol metabolism in rats and guinea-pigs Fears, R., R. Brown, et al. (1990), Biochem Pharmacol 40(9): 2029-37. Abstract: Novel bile salts (quaternary ammonium conjugates) inhibited cholic acid binding and transport in everted ileal sacs in vitro. The cationic piperazine conjugate of lithocholic acid (di-iodide salt, compound 8, BRL 39924A) appeared most active, inhibiting binding by 29% and transport by 59% in guinea-pig ileum (200 microM). BRL 39924A also inhibited taurocholate uptake into guinea-pig ileal sacs and cholate uptake into rat ileal sacs and was selected for further study in vivo. In hyperlipidaemic rats, BRL 39924A significantly raised cholesterol 7 alpha-hydroxylase activity and decreased hepatic accumulation of exogenous cholic acid. HDL cholesterol concentration in the serum increased and the level of VLDL plus LDL cholesterol decreased. In hyperlipidaemic guinea-pigs. BRL 39924A lowered serum total cholesterol and triglyceride levels. Although metabolic changes were less than those achieved with the bile acid sequestrant, cholestyramine, the doses of BRL 39924A used were much lower (100-500 mg/kg body wt). Selective inhibition of receptor mediated bile acid uptake may be associated with local side-effects but these novel bile salts are useful pharmacological tools to examine the effects of receptor blockade on lipoprotein metabolism. |
| Effects of novel synthetic sterol probes on enzymes of cholesterol metabolism in cell-free and cellular systems Harte, R. A., S. J. Yeaman, et al. (1996), Chem Phys Lipids 83(1): 45-59. Abstract: A series of novel sterols was synthesised as probes for the enzymatic and cellular functions of two important enzymes of intracellular cholesterol metabolism, acyl-CoA:cholesterol acyltransferase (ACAT) and cholesterol 7 alpha-hydroxylase. The compounds were 6-fluoro-5-cholesten-3 beta-ol (6-fluorocholesterol), 7-cholesten-3 beta-ol (7-cholestenol), 6 beta-fluorocholestan-3 beta-ol (6 beta-fluorocholestanol), 3-acetoxy-6-fluorocholestan-3 beta-ol (3-acetoxy-6-fluorocholestanol) and 7-methoxy-5-cholesten-3 beta-ol (7-methoxycholesterol). They were designed to reveal the effect of small changes in sterol structure, particularly reactivity of certain parts of the ring structure and polarity, on enzyme activity and intracellular cholesterol metabolism. The 3 beta-hydroxy group was essential for interaction with both enzymes since 3-acetoxy-6-fluorocholestanol did not affect any of the enzyme-catalysed reactions. 6-Fluorocholesterol and 7-cholestenol had no effect on cholesterol esterification but did inhibit the hydroxylation of cholesterol, as did the other compounds with groups that could influence the 7 position, namely 6 beta-fluorocholestanol and 7-methoxycholesterol. The fluorocholestanols were all competitive substrates for cholesterol esterification in cell-free and cellular assays of ACAT activity. 7-Methoxycholesterol was a surprisingly effective inhibitor of ACAT for a simple sterol. However, 6-fluorocholesterol did not have any effect on ACAT, suggesting that interactions between the enzyme and the region around C-6 and C-7 of the sterol are important. These results show that it is possible to dissect components of cholesterol metabolism using simple, specifically substituted sterols and thus define a new approach to studying the relationships between the various enzymes that catalyse intracellular cholesterol metabolism. |
| Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and high-density lipoprotein-induced cholesterol efflux in macrophages Azuma, Y., T. Kawasaki, et al. (1999), Jpn J Pharmacol 79(2): 159-67. Abstract: We investigated the effects of a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, NTE-122 (trans-1,4-bis1-cyclohexyl-3-(4-dimethylamino phenyl)ureidomethylcyclohexane), on ACAT activities in macrophages originating from several species and high-density lipoprotein (HDL)-induced cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. NTE-122 inhibited cell-free ACAT activities in human PMA-treated THP-1 cells and mouse J774.1 cells with IC50 values of 0.88 and 360 nM, respectively. NTE-122 competively inhibited the ACAT activity in PMA-treated THP-1 cells. NTE-122 also inhibited cellular ACAT activities in PMA-treated THP-1 cells, rat peritoneal macrophages and J774.1 cells with IC50 values of 3.5, 84 and 6800 nM, respectively. Furthermore, NTE-122 prevented cholesterol accumulation in PMA-treated THP-1 cells incubated with acetylated low density lipoprotein, simultaneously with HDL, while it caused accumulation of a significant amount of free cholesterol in the absence and even in the presence of HDL. NTE-122 also enhanced HDL-induced cholesterol efflux from established foam cells converted from PMA-treated THP-1 cells. These results suggest that NTE-122, capable of inhibiting macrophage ACAT activity in humans more strongly than those in the other species, exhibits anti-atherogenic effects by preventing the foam cell formation and enhancing the foam cell regression in humans. |
| Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and secretions of apolipoprotein B-containing lipoprotein and bile acids in HepG2 Azuma, Y., T. Kawasaki, et al. (1999), Jpn J Pharmacol 79(2): 151-8. Abstract: We studied the effect of NTE-122 (trans-1,4-bis1-cyclohexyl-3-(4-dimethylamino phenyl) ureidomethylcyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on intracellular cholesterol esterification and the secretion of apolipoprotein B100 (apoB)-containing lipoprotein and bile acids in the human hepatoma cell line HepG2. NTE-122 markably inhibited 3Holeate incorporation into cholesteryl esters in HepG2 cells incubated with 5 microg/ml 25-hydroxycholesterol as a stimulus for ACAT (IC50=6.0 nM). On the other hand, NTE-122 did not affect 3Holeate incorporation into triglycerides and phospholipids and 14Cacetate incorporation into cholesterol. The stimulation of ACAT by 25-hydroxycholesterol caused significant increases in the secretion of radiolabeled cholesteryl esters, radiolabeled triglycerides and apoB mass. NTE-122 pronouncedly inhibited the secretion of radiolabeled cholesteryl esters in proportion to the inhibition of cellular cholesterol esterification, and it significantly reduced the secretion of radiolabeled triglycerides and apoB mass in HepG2 cells incubated with 25-hydroxycholesterol. Furthermore, NTE-122 increased the secretion of bile acids synthesized from 14C-cholesterol. These results suggest that NTE-122 is capable of exhibiting anti-hyperlipidemic effects by reducing both the cholesterol content and the amount of secreted very low-density lipoprotein and enhancing the excretion of bile acid from the liver. |