| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Influx, efflux, and accumulation of LDL in normal arterial areas and atherosclerotic lesions of white Carneau pigeons with naturally occurring and cholesterol-aggravated aortic atherosclerosis Schwenke, D. C. and R. W. St Clair (1993), Arterioscler Thromb 13(9): 1368-81. Abstract: This study investigated the hypothesis that increased influx of low-density lipoprotein (LDL) accounts for the natural development of atherosclerosis in a characteristic (susceptible) site in the distal thoracic aorta of White Carneau (WC) pigeons and the exacerbation of atherosclerosis by cholesterol feeding. The influence of dietary cholesterol-induced changes in LDL composition on LDL influx into the artery was also investigated. As a measure of the influx of LDL into the artery, we determined the arterial accumulation of radiolabeled LDL after 1 hour. Nine 50-month-old WC pigeons with naturally occurring atherosclerosis and seven 14-month-old WC pigeons with atherosclerosis accelerated by 10 months of cholesterol feeding were studied. In the absence of atherosclerotic lesions, we found no evidence for increased accumulation of LDL at the susceptible site. In fact, more LDL accumulated in less susceptible normal arterial areas near the heart (approximately 90 nl/h per square centimeter) than in the susceptible distal thoracic aorta (approximately 35 nl/h per square centimeter). In the absence of atherosclerotic lesions, LDL accumulation (nanoliters per hour per square centimeter) was not influenced by hypercholesterolemia, although mass transport of LDL cholesterol into the artery was increased. Naturally occurring atherosclerotic lesions accumulated five times as much LDL as the adjacent normal arterial area (P <.001), whereas cholesterol-aggravated atherosclerotic lesions in different arterial sites accumulated four to 26 times as much LDL as the adjacent normal artery (P <.05). Cholesterol-aggravated atherosclerotic lesions at the most susceptible site accumulated five times as much LDL as naturally occurring atherosclerotic lesions in the corresponding arterial site (823 +/- 241 vs 175 +/- 45 nl/h per square centimeter, mean +/- SEM; P <.005). Arterial accumulation of LDL was influenced very little by changes in LDL composition induced by cholesterol feeding. In another study with young WC pigeons free of atherosclerosis and other WC pigeons with cholesterol-aggravated atherosclerosis, we injected differently labeled LDL 0.5 and 1 hour before sacrifice to investigate whether efflux of LDL from the artery was significant during a 1-hour period of LDL uptake. Although efflux of LDL from all arterial sites occurred during 1 hour, differential efflux could not account for regional differences in 1-hour arterial LDL accumulation. This study suggests that the characteristic susceptibility of the distal thoracic aorta of WC pigeons to atherosclerosis and the exacerbation of atherosclerosis by cholesterol feeding cannot be explained by differences in influx or efflux of LDL.(ABSTRACT TRUNCATED AT 400 WORDS) |
| Information on cholesterol levels in children and adolescents in Spain. Groups of Experts of the Spanish Society of Arteriosclerosis, Cardiology, Pediatrics, Nutrition and Preventive Medicine Plaza Perez, I. (1991), An Esp Pediatr 35 Suppl 46: 169-75. |
| Information on cholesterol program Kawada, T. (2002), Percept Mot Skills 94(2): 670. Abstract: Factors in low cholesterol values among elderly require very careful monitoring and attention during treatment. |
| Information sessions for outpatients referred to a hospital Nutrition and Dietetic Service for cholesterol lowering advice Reid, V., E. Barnes, et al. (2002), J Hum Nutr Diet 15(4): 281-6. Abstract: AIM: To assess the feasibility of recruiting outpatients referred for cholesterol lowering advice to attend a 1-h evening information session provided by a hospital dietitian and to evaluate the service. METHOD: A Cholesterol Information Session was held on one evening each month between April and September 2000. Patients referred to the Nutrition and Dietetic Service for cholesterol lowering advice were sent appointments for these sessions by post instead of a one-to-one daytime appointment with the dietitian. At the session, the dietitian explained what cholesterol is and gave advice about the healthy eating and lifestyle changes needed to control it. Video material and literature were used to support verbal information. Questions were encouraged throughout the session. RESULTS: Thirty-four patients were sent appointments. Twenty-seven (79%) attended, 10 of whom were accompanied by a spouse/partner/carer/family member. All patients who attended completed evaluation forms. There was a high level of satisfaction with the sessions. Twenty-six patients (96%) said they liked the way the session was run and found the advice and videos helpful. Twenty-five patients (93%) preferred the evening appointment to a day time one. Patients who attended with a spouse/partner/carer/family member indicated it was helpful to them and the accompanying person. Feedback through patient comments was positive. The seven patients (21%) who did not attend the sessions made contact with the dietetic service. CONCLUSION: As a result of the positive outcome of the evaluation, the Cholesterol Information Session is continuing as a service to patients. It provides a facility outside the usual hours of outpatient services and can readily accommodate accompanying people. The information session uses the group format, which may be applicable to other specialist areas of the Nutrition and Dietetic service in the future, such as diabetes management. |
| Infralabyrinthine approach for cholesterol granuloma of the petrous apex Mosnier, I., H. Wu, et al. (2000), Ann Otolaryngol Chir Cervicofac 117(3): 174-82. Abstract: Cholesterol granuloma of the petrous apex are cystic lesions, revealed by otologic and/or cranial nerve palsies, and diagnosed with the help of computed tomography and magnetic resonance imaging. Surgical treatment is not the complete removal of the lesion, but a conservative approach requiring drainage of the cyst and re-establishment of a correct aeration of the cavity. Three cases of cholesterol granuloma of the petrous apex were treated through a transmastoid infralabyrinthine procedure. Through a postauricular approach, a simple mastoidectomy was performed. The third portion of the facial nerve was identified. The posterior and lateral semicircular canals, and the jugular bulb were skeletonized. In two cases, a high diverticulum of the jugular bulb was impacted downwards with wax. The cystic lesion was then opened, and evacuated. The opening must be large to permit a correct aeration of the cavity and prevent stenosis of the drainage site. Hearing and the facial function were preserved in all cases. In conclusion, conservative approach to cholesterol granuloma of the petrous apex provides satisfactory drainage of this intrapetrous deep seated lesion with preservation of hearing and facial nerve function. |
| Infrared spectroscopic studies on the phosphatidylserine bilayer interacting with calcium ion: effect of cholesterol Choi, S., W. Ware, Jr., et al. (1991), Biochemistry 30(35): 8563-8. Abstract: Fourier transform infrared (IR) spectroscopic studies of phosphatidylserine/cholesterol/Ca2+ complexes are reported using the synthetic phosphatidylserines (PS) 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS), and 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS). IR spectra reveal that cholesterol does not significantly alter the binding nature of Ca2+ to PS molecules; Ca2+ binds to the phosphate ester group of PS in the presence of cholesterol up to 50 mol% as in the case of pure PS bilayers. However, the IR data indicate that the presence of cholesterol induces disorder of the acyl chain packing, increases the degree of immobilization of the interfacial and polar regions, and increases the degree of dehydration of the PS/Ca2+ complexes. |
| Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption Gylling, H. and T. A. Miettinen (2002), J Lipid Res 43(9): 1472-6. Abstract: Heredity of cholesterol absorption and synthesis was studied in siblings of hypercholesterolemic probands with low and high serum cholestanol to cholesterol ratio (assumed to indicate low and high absorption of cholesterol, respectively). Cholesterol synthesis was assayed with sterol balance technique and measuring serum cholesterol precursor to cholesterol ratios (synthesis markers of cholesterol), and cholesterol absorption with measuring dietary cholesterol absorption percentage and serum plant sterol and cholestanol to cholesterol ratios (absorption markers of cholesterol). In the siblings of the low absorption families, cholesterol absorption percentage and ratios of absorption markers were significantly lower, and cholesterol and bile acid synthesis, cholesterol turnover, fecal steroids and ratios of synthesis markers significantly higher than in the siblings of the high absorption families. The ratios of absorption and synthesis markers were inversely interrelated, and they were correlated with cholesterol absorption and synthesis in the siblings. In addition, low absorption was associated with high body mass index, low HDL cholesterol, and serum sex hormone binding globulin levels, suggesting that low absorption was associated with metabolic syndrome. Intrafamily correlations were significant for serum synthesis markers, cholestanol, triglycerides, and blood glucose level. In conclusion, cholesterol absorption efficiency and synthesis are partly inherited phenomena, and they can be predicted by the ratios of non-cholesterol sterols to cholesterol in serum. |
| Inherited disorders of cholesterol biosynthesis Haas, D., R. I. Kelley, et al. (2001), Neuropediatrics 32(3): 113-22. Abstract: Defects of cholesterol biosynthesis comprise a heterogeneous group of disorders, most of which have only been recently described and more are likely to follow in the near future.Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) are due to allelic defects in mevalonate kinase, an enzyme located proximally in the pathway of cholesterol and nonsterol isoprene biosynthesis. Clinically, patients affected with these disorders present with recurrent febrile attacks. This is the only manifestation in most patients with HIDS, and, in the case of classical mevalonic aciduria, is part of a severe multisystemic disease, including malformations, severe failure to thrive and neurological abnormalities. The other recognized defects of cholesterol biosynthesis are due to enzyme defects located distally in the pathway beyond the branching points of nonsterol isoprene biosynthesis and solely affecting cholesterol biosynthesis. Patients with these disorders all present with complex malformation syndromes involving different organ systems. The main characteristics of CHILD syndrome and Conradi-Huenermann syndrome are skeletal defects and ichthyosiform skin involvement. Smith-Lemli-Opitz syndrome and desmosterolosis are generalized malformation syndromes involving many different organs including the central nervous system.The diagnosis of MVA and HIDS is based on determination of mevalonic acid in urine followed by determination of enzyme activity, whereas the search for the distally located defects of cholesterol biosynthesis requires sterol analysis in blood or tissues by GCMS.Rational therapeutic approaches have been described for HIDS, MVA and Smith-Lemli-Opitz syndrome. |
| Inherited disorders of cholesterol biosynthesis Waterham, H. R. (2002), Clin Genet 61(6): 393-403. Abstract: For many decades, cholesterol has been considered an important structural component of cellular membranes and myelin, and a precursor of steroid hormones and bile acids. Moreover, the recognition that high cholesterol levels (hypercholesterolemia) are a major risk factor for the development of heart disease and atherosclerosis has gained enormous attention not only in medicine, medical and pharmacological research, but also from the general public. The discovery of a crucial role of cholesterol in human embryogenesis and the recent identification of a number of inherited disorders of cholesterol biosynthesis also show that low cholesterol levels (hypocholesterolemia) may have severe consequences for human health and development. In the past few years, seven distinct inherited disorders have been linked to different enzyme defects in the cholesterol biosynthetic pathway by the finding of abnormally increased levels of intermediate metabolites in patients followed by the demonstration of disease-causing mutations in genes encoding the implicated enzymes. Patients afflicted with these disorders are characterized by multiple morphogenic and congenital anomalies including internal organ, skeletal and/or skin abnormalities. |
| Inherited low serum HDL-cholesterol levels and anemia--the first Finnish LCAT-deficient family Gylling, H., E. Ikkala, et al. (1993), Duodecim 109(9): 751-7. |
| Inhibiting cholesterol absorption with CP-88,818 (beta-tigogenin cellobioside; tiqueside): studies in normal and hyperlipidemic subjects Harris, W. S., C. A. Dujovne, et al. (1997), J Cardiovasc Pharmacol 30(1): 55-60. Abstract: CP-88,818 (beta-tigogenin cellobioside; tiqueside) is a synthetic saponin developed to treat hypercholesterolemia by inhibiting the absorption of biliary and dietary cholesterol. Two studies are reported here: one in patients to assess safety and efficacy, and one in normal volunteers to explore the mechanism of action. The former included 15 hypercholesterolemic outpatients low-density lipoprotein cholesterol (LDL-C) > or = 160 mg/dl treated with 1, 2, and 3 g of tiqueside daily (b.i.d.) in a crossover design for three 2-week treatment periods, each separated by a 3-week placebo period. The mechanistic study was conducted with 24 healthy male subjects who were randomized in a parallel group design to either placebo (n = 6) or tiqueside (2 or 4 g/day; n = 9 each) once daily for 3 weeks. All subjects in this study were fed a low-fat, low-cholesterol diet National Cholesterol Education Program (NCEP) Step 1. Fecal steroid excretion rates and plasma lipid levels were determined at baseline and after 3 weeks of treatment. Fractional cholesterol absorption was measured before and after treatment by the continuous feeding, dual-isotope method. Tiqueside produced a dose-dependent reduction in plasma LDL cholesterol levels in the hypercholesterolemic patients. In the mechanistic study, it decreased fractional cholesterol absorption rates and increased fecal neutral sterol excretion rates, changes associated with trends toward lower LDL cholesterol levels. Other lipoprotein levels were unaffected, as were fecal fat and bile acid excretion and fat-soluble vitamin absorption. Thus tiqueside dose-dependently inhibits cholesterol absorption in humans, resulting in a reduction in serum LDL cholesterol levels. |
| Inhibiting cholesterol synthesis reduces the binding and toxicity of amphotericin B against rabbit renal tubular cells in primary culture Joly, V., M. Saint-Pierre-Chazalet, et al. (1992), J Infect Dis 165(2): 337-43. Abstract: Renal tubular cells are a target of amphotericin B (AmB) toxicity, but the mechanisms involved in the tubular cell-AmB interactions are unknown. Ketoconazole was selected to lower the cholesterol content of rabbit renal tubular cells in primary culture. The consequences of cholesterol depletion on AmB nephrotoxicity was investigated in vitro as the inhibition of Na(+)-dependent phosphate uptake. After 1 h of exposure, AmB decreased phosphate uptake (49%, 77%, and 82% inhibition with 5, 10, and 20 microM of AmB, respectively). Pretreatment of cells with ketoconazole (10 microM for 24 h) reduced by 50% (P less than.01) the phosphate uptake inhibition induced by AmB, decreased cellular cholesterol synthesis (greater than 80% inhibition), and decreased AmB binding to cell membrane by 50%, as measured by the fluorescence extinction of a probe bound to tubular cell membrane. Incubation with exogenous exchangeable cholesterol again increased AmB binding to plasma membrane and restored AmB toxicity. These results demonstrate that the first step of AmB renal tubular toxicity is mediated by cellular cholesterol content and is parallel to the binding of AmB to cell membrane. |
| Inhibition and promotion of cholesterol crystallization by protein fractions from normal human gallbladder bile Busch, N., N. Matiuck, et al. (1991), J Lipid Res 32(4): 695-702. Abstract: Pooled, normal human gallbladder biles were initially separated on a molecular sieving chromatography column to remove soluble mucin glycoproteins as well as high molecular weight proteins (greater than 200,000). The remaining lower molecular weight proteins and other bile components were then examined by lectin affinity chromatography with four different types of lectin. The separated bound fractions were compared for inhibiting and promoting activities with a newly devised sensitive cholesterol crystal growth assay and for differences in electrophoretic patterns on SDS-gels. Protein factors (presumably glycoproteins) were found to have both inhibiting and promoting activities, even in the absence of cholesterol gallstone disease. The promoting effect was indicated by shortened crystal detection times and increases in crystal growth rate; whereas the inhibiting effect was indicated by decreases in crystal growth rate and reductions in the final crystal concentration as determined by the growth assay. Affinity chromatography mitigated the major problems of removing both lipids and pigment from the glycoproteins. In addition, partial purification of bound fractions with potent cholesterol crystal nucleation-altering activity can be obtained by this technique. |
| Inhibition by cholesterol oxides of NO release from human vascular endothelial cells Deckert, V., A. Brunet, et al. (1998), Arterioscler Thromb Vasc Biol 18(7): 1054-60. Abstract: Recent studies have demonstrated that, unlike cholesterol, cholesterol oxidized at position 7 can reduce the maximal endothelium-dependent relaxation of isolated rabbit aortas (Circulation. 1997;95:723-731). The aim of the current study was to determine whether cholesterol oxides reduce the release of nitric oxide (NO) from human umbilical vein endothelial cells (HUVECs). The amount of NO released by histamine-stimulated HUVECs was determined by differential pulse amperometry using a nickel porphyrin- and Nafion-coated carbon microfiber electrode. The effects of cholesterol (preserved from oxidation by butylated hydroxytoluene), 7-ketocholesterol, 7beta-hydroxycholesterol, 5alpha,6alpha-epoxycholesterol, 19-hydroxycholesterol (60 microg/mL), and alpha-lysophosphatidylcholine (10 microg/mL) were compared. Pretreatment of HUVECs with cholesterol, 5alpha,6alpha-epoxycholesterol, or 19-hydroxycholesterol did not alter histamine-activated NO production. In contrast, pretreatment with 7-ketocholesterol or 7beta-hydroxycholesterol significantly decreased NO release. The inhibitory effect of 7-ketocholesterol was time and dose dependent and was maintained in the presence of L-arginine. In the absence of serum, lysophosphatidylcholine also reduced NO production. In ionomycin-stimulated cells, pretreatment with 7-ketocholesterol did not inhibit NO release. These results demonstrate that cholesterol derivatives oxidized at the 7 position, the main products of low density lipoprotein oxidation, reduce histamine-activated NO release in HUVECs. Such an inhibitory effect of cholesterol oxides may account, at least in part, for the ability of oxidized low density lipoprotein to reduce the endothelium-dependent relaxation of arteries. |
| Inhibition of 3-hydroxy-3-methylglutaryl-CoA synthase and cholesterol biosynthesis by beta-lactone inhibitors and binding of these inhibitors to the enzyme Greenspan, M. D., H. G. Bull, et al. (1993), Biochem J 289 (Pt 3): 889-95. Abstract: The beta-lactones L-659,699 (E,E)-11-3-(hydroxymethyl)-4-oxo-2- oxetanyl-3,5,7-trimethyl-2,4-undecadienoic acid) and its radioactive derivative 3H-L-668,411 (the 2,3-ditritiated methyl ester of L-659,699) inhibited a partially purified preparation of rat liver cytosolic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase with an IC50 of 0.1 microM. These compounds were also found to inhibit the incorporation of 14Cacetate into sterols in cultured Hep G2 cells with an IC50 of 3 microM. New kinetic evidence indicated that inhibition of the isolated enzyme was irreversible. In contrast, sterol biosynthesis in cultured Hep G2 cells was rapidly restored upon removal of the compound from the medium of inhibited cultures, suggesting reversibility of inhibition in the cells. Radioactivity was found to be associated with a single cytoplasmic protein by SDS/PAGE of the cytoplasm of Hep G2 cells after incubation of the cells with the inhibitor 3H-L-668,411. This protein was identified as cytoplasmic HMG-CoA synthase. Binding of the radioactive compound to the enzyme was decreased with time if the radioactive inhibitor was removed from the medium. Exposure of a gel containing the radioactive enzyme-inhibitor complex to neutral hydroxylamine also resulted in a loss of radioactivity from the gel. The purified rat liver enzyme reacted with the 3H-ligand to form a stable enzyme-inhibitor complex which could be isolated by h.p.l.c. Radioactivity was also subsequently lost from this complex when it was incubated with neutral hydroxylamine. Incorporation of 14Cacetate into cholesterol in mouse liver was inhibited in a reversible manner after oral administration of the beta-lactone inhibitor. These studies, as well as the kinetic evidence presented, suggest that the beta-lactone inhibitors acylate HMG-CoA synthase in a reaction which appears to be irreversible in vitro, but is easily reversed in cultured cells and in animals. |
| Inhibition of ACAT activity after 7-oxo-PGI2 treatment in cholesterol-fed rabbits Makary, A., E. Kolthay, et al. (1992), Exp Toxicol Pathol 44(2): 105-7. Abstract: It has been supposed that prostacyclin (PGI2) and its analogues have important antiatherogenic effects. The aim of this work was to test the effect of PGI2 and 7-oxo-PGI2- (a stable analogue of PGI2) (6) treatment on the acyl CoA: cholesterol-acyltransferase (ACAT) activity in the aortic wall of rabbits. The rabbits had been previously fed with cholesterol and treated with PGI2 and 7-oxo-PGI2 intravenously. Cholesterol feeding increased ACAT activity compared to the control group which was not fed with cholesterol: 16.84 nmol/mg prot./h and 10.03 nmol/mg prot./h, respectively. PGI2 treatment of the cholesterol fed group did not cause a significant decrease, while 7-oxo-PGI2 treatment significantly decreased aortic ACAT activity compared to the cholesterol-fed control group; 14.31 nmol/mg prot./h; 11.53 nmol/mg prot./h and 16.84 nmol/mg prot./h, respectively. The decrease found in the ACAT activity after PGI2 and 7-oxo-PGI2 treatment are new data for the protective effect of these agents against atherosclerosis. |
| Inhibition of acyl coenzyme A: cholesterol acyl transferase by trimethylcyclohexanylmandelate (cyclandelate) Heffron, F., B. Middleton, et al. (1990), Biochem Pharmacol 39(3): 575-80. Abstract: Cyclandelate was an effective inhibitor of rat hepatic acycloenzyme A: cholesterol acyltransferase (ACAT) with a concentration of 80 microM being required for half maximal inhibition. A similar effect was seen with human and rabbit liver microsomal enzymes. The drug did not compete with oleoyl CoA or cholesterol and could be removed from enzyme preparations by washing. It was hydrolysed rapidly by rat liver microsomes to products which were non inhibitory. No hydrolysis of the drug was seen with non hepatic microsomes and the concentration of cyclandelate required to cause half maximal inhibition of ACAT in the transformed mouse macrophage J774 microsomal fraction was less than 30 microM. The possible significance of the differential actions of cyclandelate towards hepatic and extra hepatic ACAT in vivo is discussed. |
| Inhibition of acyl coenzyme A:cholesterol acyltransferase blocks esterification but not uptake of cholesterol in Caco-2 cells Ellsworth, J. L. and J. R. Starr (1998), Metabolism 47(3): 325-32. Abstract: The effects of cholesterol esterase (CEase) and acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on the uptake and esterification of cholesterol in Caco-2 cells were examined. CEase increased the uptake of 3Hcholesterol from bile salt mixed-micelles by 2.5- to 3.0-fold and its esterification by greater than 25-fold. Inhibition of cellular ACAT activity with CL277082 or CP113818 had little or no effect on cholesterol uptake measured in the presence or absence of CEase. The subsequent esterification of 3Hcholesterol was reduced greater than 90% by each ACAT inhibitor. Similar results were obtained in cells in which ACAT activity was induced by preincubation either with 25-hydroxycholesterol and mevalonic acid or with CEase and bile salt mixed-micelles containing 100 micromol/L cholesterol. Neither ACAT inhibitor had an effect on CEase-mediated synthesis or hydrolysis of cholesteryl oleate in vitro. Thus, the uptake of cholesterol from bile salt mixed-micelles in the presence or absence of CEase was not regulated by the level of cellular ACAT expression. The subsequent esterification of exogenous sterol was not due to CEase, but was completely dependent on ACAT activity. The dissociation of cholesterol uptake from ACAT activity suggests that the factors controlling the transfer of sterol from extracellular media to the cell are different from the factors regulating the cellular level of cholesterol esterification. |
| Inhibition of acyl-CoA cholesterol O-acyltransferase reduces the cholesteryl ester enrichment of atherosclerotic lesions in the Yucatan micropig Bocan, T. M., S. B. Mueller, et al. (1993), Atherosclerosis 99(2): 175-86. Abstract: Atherosclerotic lesion development may be altered indirectly by regulating plasma cholesterol or directly by inhibition of acyl-CoA cholesterol O-acyltransferase (ACAT) within cells of the artery. Yucatan micropigs were meal-fed a 2% cholesterol, 8% peanut oil, 8% coconut oil purified diet for 1 month prior to administration of the potent, bioavailable ACAT inhibitor CI-976, and induction of atherosclerotic lesions by chronic endothelial damage. After 84-108 days of therapy, CI-976 decreased mean plasma VLDL-cholesterol 85-91% and cumulative VLDL-exposure (area under VLDL-time curve) by 65%. However, overall plasma total, LDL and HDL cholesterol and triglyceride levels were unchanged. CI-976 decreased liver cholesteryl ester (CE) content 65% without significantly affecting adrenal CE content. The CE content of the injured left femoral, left iliac and abdominal aorta and uninjured right femoral and iliac arteries and thoracic aorta was reduced 62-78% by CI-976. Systemic plasma CI-976 levels measured 24 h post-dose ranged from 2.26 to 4.05 micrograms/ml and significantly correlated with the reduction in both VLDL and vessel CE content. Thus, we conclude that inhibition of ACAT can blunt the cholesteryl ester enrichment of developing atherosclerotic lesions by preventing reesterification and storage of lipoprotein cholesterol within vascular cells and by reducing the plasma level and delivery to the arterial wall of such atherogenic lipoproteins as VLDL. |
| Inhibition of acyl-CoA: cholesterol acyltransferase activity by cyclodepsipeptide antibiotics Tomoda, H., X. H. Huang, et al. (1992), J Antibiot (Tokyo) 45(10): 1626-32. Abstract: The effect was studied of the fungal cyclodepsipeptide antibiotics beauvericin and seven distinct enniatins on acyl-CoA: cholesterol acyltransferase (ACAT) activity. In an enzyme assay using rat liver microsomes, all the compounds were found to inhibit ACAT activity. The drug concentration that caused 50% inhibition (IC50 value) of the enzyme activity was determined to be 3.0 microM for beauvericin, indicating that the compound is one of the most potent ACAT inhibitors of microbial origin. Enniatins exhibited much higher IC50 values of 22 to 110 microM. More hydrophobic enniatins showed more potent inhibitory activity. Furthermore, the ACAT inhibitory activity was evaluated as inhibition of cholesteryl ester formation in a cell assay using J774 macrophages. Calculation of the ratio, CD50 value (the drug concentration causing 50% cell damage)/IC50 value of cholesteryl ester formation, indicated that beauvericin shows the highest specificity. These data indicate that beauvericin is one of the most potent and specific ACAT inhibitors of microbial origin. |