| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Chromosomal organization of candidate genes involved in cholesterol gallstone formation: a murine gallstone map Lammert, F., M. C. Carey, et al. (2001), Gastroenterology 120(1): 221-38. Abstract: Epidemiologic and family studies indicate that cholesterol gallstone formation is in part genetically determined. The major contribution to our current understanding of gallstone genes derives from animal studies, particularly cross-breeding experiments in inbred mouse strains that differ in genetic susceptibility to cholesterol gallstone formation (quantitative trait loci mapping). In this review we summarize how the combined use of genomic strategies and phenotypic studies in inbred mice has proven to be a powerful means of dissecting the complex pathophysiology of this common disease. We present a "gallstone map" for the mouse, consisting of all genetic loci that have been identified to confer gallstone susceptibility as well as putative candidate genes. Translation of the genetic loci and genes between mouse and human predicts chromosomal regions in the human genome that are likely to harbor gallstone genes. Both the number and the precise understanding of gallstone genes are expected to further increase with rapid progress of the genome projects, and multiple new targets for early diagnosis and prevention of gallstone disease should become possible. |
| Chronic administration of eicosapentaenoic acid and docosahexaenoic acid as ethyl esters reduced plasma cholesterol and changed the fatty acid composition in rat blood and organs Froyland, L., H. Vaagenes, et al. (1996), Lipids 31(2): 169-78. Abstract: Fish oils rich in n-3 fatty acids have been shown to decrease plasma lipid levels, but the underlying mechanism has not yet been elucidated. This investigation was performed in order to further clarify the effects of purified ethyl esters of eicosapentaenoic acid (EPA-EE) and docosahexaenoic acid (DHA-EE) on lipid metabolism in rats. The animals were fed EPA-EE, DHA-EE, palmitic acid, or corn oil (1 g/kg/d) by orogastric intubation along with a chow background diet for three months. At the end the animals were sacrificed. Plasma and liver lipids were measured, as well as lipid-related enzyme activities and mRNA levels. The fatty acid composition of plasma and different tissues was also determined. This study shows that, compared to the corn oil control, EPA-EE and DHA-EE lowered plasma cholesterol level, whereas only EPA-EE lowered the amount of plasma triacylglycerol. In liver peroxisomes, both EE preparations increased fatty acyl-CoA oxidase FAO activities, and neither altered 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activities. In liver microsomes, EPA-EE raised HMG-CoA reductase and acyl-CoAicholesterol acyltransferase activities, whereas DHA-EE lowered the former and did not affect the latter. Neither product altered mRNA levels for HMG-CoA reductase, low density lipoprotein-receptor, or low density lipoprotein-receptor related protein. EPA-EE lowered plasma triacylglycerol, reflecting lowered very low density lipoprotein secretion, thus the cholesterol lowering effect in EPA-EE-treated rats may be secondary to the hypotriacylglycerolemic effect. An inhibition of HMG-CoA reductase activity in DHA-EE treated rats may contribute to the hypocholesterolemic effect. The present study reports that 20:5n-3, and not 22:6n-3, is the fatty acid primarily responsible for the triacylglycerol lowering effect of fish oil. Finally, 20:5n-3 was not converted to 22:6n-3, whereas retroconversion of 22:6n-3 to 20:5n-3 was observed. |
| Chronic administration of the cholesterol reducing drug gemfibrozil fails to alter 5-HT1A and 5-HT2A mediated receptor behaviours in rats McCreary, A. C. and S. L. Handley (2000), J Psychopharmacol 14(3): 280-3. Abstract: Some studies have suggested that reductions in plasma cholesterol might be associated with suicidal behaviour. Serotonergic systems are thought to be involved in suicidal ideation and behaviour and links with altered 5-HT1A and 5-HT2A receptors have been proposed. We have therefore examined the effects of cholesterol reduction using gemfibrozil, upon 5-HT2A and 5-HT1A receptor-related behaviours in rats. Rats were treated chronically (57 days) with gemfibrozil (50 mg/kg p.o.) or gum acacia vehicle and challenged sequentially with the 5-HT1A agonist 8-hydroxy-d-n-aminopropyl tetralin, to elicit 5-HT1A syndrome behaviours, and the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane to establish their head-shake frequency. Significant cholesterol reduction, within the clinical range, failed to induce any changes in either 5-HT1A or 5-HT2A mediated behaviours. These data suggest that cholesterol reduction fails to induce changes in 5-HT1A and 5-HT2A receptor tone suggesting that the reduction of plasma cholesterol, within the human clinical range, does not result in neuroplasticity of the 5-HT1A and 5-HT2A receptors in rats. |
| Chronic antidepressant treatment prevents accumulation of gsalpha in cholesterol-rich, cytoskeletal-associated, plasma membrane domains (lipid rafts) Donati, R. J. and M. M. Rasenick (2005), Neuropsychopharmacology 30(7): 1238-45. Abstract: Previous studies demonstrated that Gsalpha migrates from a Triton X-100 (TTX-100) insoluble membrane domain to a TTX-100 soluble membrane domain in response to chronic treatment with the antidepressants desipramine and fluoxetine. Antidepressant treatment also causes a Gsalpha redistribution in cells as seen by confocal microscopy. The current studies have focused on examining the possibility that the association between Gsalpha and the plasma membrane and/or cytoskeleton is altered in response to antidepressant treatment, and that this is relevant to both Gsalpha redistribution and the increased coupling between Gsalpha and adenylyl cyclase seen after chronic antidepressant treatment. Chronic treatment of C6 cells with two fuctionally and structurally distinct antidepressants, desipramine and fluoxetine, decreased the Gsalpha content of TTX-100 insoluble membrane domains by as much as 60%, while the inactive fluoxetine analog LY368514 had no effect. Disruption of these membrane domains with the cholesterol chelator methyl-beta-cyclodextrin altered the localization of many proteins involved in the cAMP signaling cascade, but only Gsalpha localization was altered by antidepressant treatment. In addition, microtubule disruption with colchicine elicited the movement of Gsalpha out of detergent-resistant membrane domains in a manner identical to that seen with antidepressant treatment. The data presented here further substantiate the role of Gsalpha as a major player in antidepressant-induced modification of neuronal signaling and also raise the possibility that an interaction between Gsalpha and the cytoskeleton is involved in this process. |
| Chronic intravenous aminobisphosphonate therapy increases high-density lipoprotein cholesterol and decreases low-density lipoprotein cholesterol Adami, S., V. Braga, et al. (2000), J Bone Miner Res 15(3): 599-604. Abstract: Nowadays, bisphosphonates are considered the drugs of choice for the treatment of several bone disorders. Their exact mechanism of action is not clear but recently it has been reported that the aminobisphosphonates inhibit cholesterol biosynthesis and that this might be relevant for their actions on bone osteoclasts. The study includes 87 postmenopausal women with moderate to severe osteoporosis. The patients were randomly assigned to intravenous (iv) infusion of 50 mg of the aminobisphosphonate Neridronate dissolved in 100 ml of saline solution every 2 months for a year (44 patients). The remaining 43 served as controls. At the time of each infusion blood samples were obtained for the evaluation of total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (Apo A-I), apolipoprotein B (Apo B), and total and bone alkaline phosphatase (AP). Free deoxypyridinoline (f-DPD) was measured in fasting urine specimens. In the control group no significant changes were observed throughout the study period for any of the biochemical variables. In the Neridronate-treated patients both bone AP and f-DPD excretion fell significantly by 15-20%. In these patients serum total cholesterol and serum triglycerides showed marginal decreases, which were occasionally significant. LDL-C and Apo B fell by 5-6% and these changes were statistically significant at most time points. Apo A-I and HDL-C rose progressively with time. At the 12th month, HDL-C rose 17-18% (p < 0.0001) above the baseline values. Similar findings were obtained in four postmenopausal women given high iv doses of Pamidronate or Alendronate. In conclusion aminobisphophonates, at least when given iv, induce remarkable and unexpected effects on lipid metabolism with a final profile that might be clinically relevant. |
| Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits Mugge, A., J. H. Elwell, et al. (1991), Circ Res 69(5): 1293-300. Abstract: The endothelium-derived relaxing factor is rapidly inactivated by superoxide radicals, and atherosclerotic vessels generate excess radical species. We tested the hypothesis that an imbalance between intrinsic superoxide dismutase (SOD) activity and the generation of superoxide radicals in atherosclerotic arteries may result in augmented inactivation of endothelium-derived relaxing factor. Vascular SOD was increased in normal and cholesterol-fed (1% cholesterol for 4 months) rabbits approximately twofold by treatment with polyethylene-glycolated SOD (PEG-SOD; 41,000 units/kg/day i.m.) for 1 week. Aortic rings from these animals and nontreated control and atherosclerotic rabbits subsequently were studied in organ chambers. Endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 were improved by PEG-SOD in atherosclerotic but not in normal rabbits. PEG-SOD pretreatment did not alter endothelium-independent relaxations to nitroprusside. Thus, treatment with PEG-SOD can partially restore impaired endothelium-dependent relaxation of atherosclerotic arteries. We conclude that generation of oxygen-derived radicals likely contributes to endothelial dysfunction of atherosclerotic arteries. |
| Chronically gorging v. nibbling fat and cholesterol increases postprandial lipaemia and atheroma deposition in the New Zealand white rabbit Juhel, C., Y. Pafumi, et al. (2000), Br J Nutr 83(5): 549-59. Abstract: In the present study, we compared the effects of nibbling and gorging on postprandial lipaemia and lipoproteins, hepatic lipid uptake and atheroma deposition. New Zealand White rabbits were fed on a low-fat (LF) control diet or a peanut oil- (10 g/d) and cholesterol- (0.5 g/d) enriched (HF) diet with the fat and cholesterol components given either by nibbling (HF-N) or gorging (HF-G). After 4 and 8 weeks, rabbits were given a test meal, which was either nibbled or taken as a bolus. The LF diet did not noticeably alter postprantial lipid variables. Triacylglycerol levels, 0-35 h lipid responses and plasma accumulation of dietary lipids were significantly higher in the HF-G group than in the HF-N group, despite higher post-heparin plasma lipase activities. Furthermore, as studied on cultured isolated hepatocytes, the higher the rate of supply of triacylglycerol- and cholesterol-rich lipoproteins (TCRL), the lower the rate of lipid uptake and bile salt secretion. Atheroma deposition was significantly increased by gorging the HF diet and was correlated with levels of most postprandial lipid variables. We conclude that gorging v. nibbling a fat and cholesterol-enriched diet exacerbates postprandial lipaemia by reducing the rate of TCRL clearance and favours atheroma deposition. |
| Chylomicron metabolism in normal, cholesterol-fed, and Watanabe heritable hyperlipidemic rabbits. Saturation of the sequestration step of the remnant clearance pathway Hussain, M. M., T. L. Innerarity, et al. (1995), J Biol Chem 270(15): 8578-87. Abstract: The plasma clearance of radiolabeled chylomicrons was compared in normal, cholesterol-fed, and Watanabe heritable hyperlipidemic (WHHL) rabbits. Chylomicron clearance was rapid in normal rabbits but was significantly retarded in cholesterol-fed and WHHL rabbits. At 40 min after the injection of chylomicrons, 14-17% of the injected dose remained in the plasma of normal rabbits, whereas approximately 40-50% of the injected dose remained in the plasma of cholesterol-fed and WHHL rabbits. The differences were reflected in the reduced plasma clearance by the liver and bone marrow of the cholesterol-fed and WHHL rabbits. The hyperlipidemic rabbits expressed normal levels of low density lipoprotein (LDL) receptor-related protein/alpha 2-macroglobulin receptor in the liver. In contrast, the hepatic levels of LDL receptors were lower in hyperlipidemic rabbits; as expected, they were significantly lower in WHHL rabbits compared with normal and cholesterol-fed rabbits. Furthermore, it was demonstrated that lipoproteins accumulating in the plasma of the hyperlipidemic rabbits competed for and retarded the clearance of chylomicrons from the plasma. Competition was demonstrated by cross-circulation of normal and cholesterol-fed or normal and WHHL rabbits, in which the rapid influx of plasma containing the accumulated plasma lipoproteins from cholesterol-fed or WHHL rabbits was shown to impair the uptake of chylomicrons by the liver and bone marrow of normal rabbits. These observations were extended by infusing isolated lipoproteins into normal rabbits. The rabbit d < 1.02 g/ml (remnant) fraction and the canine cholesterol-rich high density lipoproteins (HDL) with apolipoprotein E (HDLc) inhibited chylomicron clearance, whereas human LDL and HDL from humans and rabbits did not. We conclude that the low LDL receptor activity in the cholesterol-fed and WHHL rabbits may contribute, at least in part, to the impaired clearance by decreasing remnant uptake and causing the accumulation of chylomicron and/or very low density lipoprotein remnants. The accumulated remnant lipoproteins then compete for and saturate the mechanism responsible for the initial rapid clearance of chylomicrons from the plasma. We speculate that saturation of the initial rapid clearance may occur at the sequestration step, which involves the binding of remnants to heparan sulfate proteoglycans in the space of Disse. |
| Chymase in exocytosed rat mast cell granules effectively proteolyzes apolipoprotein AI-containing lipoproteins, so reducing the cholesterol efflux-inducing ability of serum and aortic intimal fluid Lindstedt, L., M. Lee, et al. (1996), J Clin Invest 97(10): 2174-82. Abstract: Degranulated mast cells are present in human fatty streaks. Chymase in granules released from degranulated rat serosal mast cells, i.e., in granule remnants, proteolyzes human high density lipoprotein3 (HDL3), and so reduces its ability to induce cholesterol efflux from macrophage foam cells in vitro. In this study we found that remnant chymase, by proteolyzing human serum and human aortic intimal fluid, prevents these two physiologic fluids from effectively inducing cholesterol efflux from cultured macrophage foam cells. Inhibition was strongest when remnants were added to apolipoprotein AI (apoAI)-containing lipoproteins; the remnants had no effect on the weaker efflux produced by apoAI-deficient serum. Western blot analysis showed that granule remnants degrade apoAI in serum and in internal fluid. When released from remnants, chymase lost its ability to proteolyze HDL3 in the presence of serum. Thus, remnant chymase (but not isolated chymase) was able to resist the natural protease inhibitors present in serum and in intimal fluid. The results imply participation of exocytosed mast cell granules in foam cell formation in atherogenesis. |
| Chymase inhibition suppresses high-cholesterol diet-induced lipid accumulation in the hamster aorta Uehara, Y., H. Urata, et al. (2002), Cardiovasc Res 55(4): 870-6. Abstract: OBJECTIVE: The role of chymase (a mast cell-derived angiotensin II-forming serine proteinase) in aortic lipid deposition was investigated using an orally active, non-peptide chymase inhibitor, SUN-C8257. METHODS: Male golden Syrian hamsters, 8 weeks old, were fed with a standard rodent meal supplemented with or without 0.5% cholesterol and 10% coconut oil for 12 weeks. The hamsters fed high cholesterol diet were further separated into two groups treated with or without SUN-C8257 for 12 weeks. The aortic lipid deposition was visualized by Oil red O staining and planimetrically measured. Immunohistochemical staining for angiotensin II (Ang II) of the aortic root region was performed. Aortic Ang II-forming activity was measured using Ang I as a substrate. Plasma total-, low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-cholesterol and triglyceride were quantified by enzymatic methods. Plasma Ang I and Ang II were measured by radioimmunoassay. RESULTS: After 12 weeks of high cholesterol diet, aortic chymase activity in the untreated group increased significantly and showed a positive correlation with plasma total- and LDL-cholesterol. This group of hamsters developed marked lipid deposits in the aortic intima. However, treatment with SUN-C8257 significantly suppressed aortic lipid deposition without changing body weight, blood pressure, plasma LDL-cholesterol and Ang II levels. The level of the adventitial Ang II-immunoreactivity was markedly inhibited in the group treated with SUN-C8257. CONCLUSION: Our results suggest that arterial chymase may participate in the acceleration of lipid deposition in arterial walls exposed to high plasma cholesterol and that inhibition of arterial chymase may retard the progression of atherosclerosis. |
| CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys Ramharack, R., M. A. Spahr, et al. (1998), Atherosclerosis 136(1): 79-87. Abstract: Lipoprotein(a) (Lp(a)), which is generated through the covalent association of apolipoprotein(a) (apo(a)) and apo B-100-LDL, is an independent risk factor for several vascular diseases. Therefore, there is interest in developing therapies for lowering Lp(a). This investigation was carried out to determine the effect of CI-1011, a potent lipid regulator in rodents, on Lp(a) and other lipid parameters in cynomolgus monkeys (Macaca fascicularis). Nine healthy male monkeys on a normal chow diet were orally treated with CI-1011 at 30 mg/kg per day for 3 weeks. Lp(a) and total cholesterol levels were significantly decreased after 1 week and maximally reduced to 68 and 73% of control levels, respectively, after 3 treatment weeks. The decreases in total cholesterol were mainly due to changes in low density lipoprotein (LDL). The LDL:HDL ratio decreased by 30%. Triglycerides were unaffected by treatment. Lp(a) and total cholesterol levels returned to pretreatment values after stopping treatment suggesting a direct effect of the compound on their inhibition. Further studies demonstrated that CI-1011 was effective at a low dose of 3 mg/kg per day after 1 week of administration. CI-1011 also decreased apo B-100 to 80% of control levels, but this change was not sufficient to account for the Lp(a) lowering. There was also no correlation between the changes in Lp(a) and apo B-100 levels. Treatment of cynomolgus monkey primary hepatocyte cultures with CI-1011 resulted in a dose-dependent inhibition of Lp(a) levels suggesting a direct hepatic effect of the compound. Western blot analysis of the samples showed that changes in Lp(a) were associated mainly with decreased apo(a) (47%), but not apo B-100 (17%). These results demonstrate that CI-1011 effectively decreases Lp(a) levels both in vivo and in vitro. |
| Cigarette smoke increases cholesterol oxidation and lipid peroxidation of human low-density lipoprotein and decreases its binding to the hepatic receptor in vitro Mahfouz, M. M., S. A. Hulea, et al. (1995), J Environ Pathol Toxicol Oncol 14(3-4): 181-92. Abstract: Low-density lipoprotein (LDL) was exposed to six puffs of cigarette smoke (CS) filtered through a glass wool filter and then incubated for 6 or 20 h at 37 degrees C. Control LDL was similarly treated but exposed to air. In cigarette smoke-treated LDL (CS-LDL), compositional changes of the lipid fraction were most detectable after 20 h incubation. These changes included a decrease of polyunsaturated fatty acids (PUFA), slight degradation of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) to their lysophospholipid lysoPE and lyso-PC, elevation of oxidized cholesterol content as well as thiobarbituric acid reacting substance (TBARS), indicating an oxidative effect of CS on LDL. CS-LDL also showed higher anodic electrophoretic mobility and crosslinking of its apoprotein by nondisulfide bonds. The binding affinity of CS-LDL to liver membrane receptor was much lower than control LDL as measured by the calcium-dependent binding of LDL-gold conjugate to the solubilized membrane protein dot blotted onto nitrocellulose strips. Our results indicate that CS induces changes in LDL, making it more atherogenic and cytotoxic. |
| Cigarette smoking and plasma cholesterol Muscat, J. E., R. E. Harris, et al. (1991), Am Heart J 121(1 Pt 1): 141-7. Abstract: Plasma cholesterol levels were determined for 51,723 participants of community-based cholesterol screenings in 10 United States cities during 1988. Among white adult men and women under the age of 60 without other cardiovascular disease risk factors, a dose-response relationship was found between the number of cigarettes smoked per day and increasing levels of plasma cholesterol. In men aged 18 to 60 years, average plasma cholesterol increased by 0.33 mg/dl for each cigarette smoked (p less than 0.001); in women aged 31 to 50 years, average plasma cholesterol increased by 0.48 mg/dl for each cigarette smoked (p less than 0.001). Plasma cholesterol levels among ex-smokers were found to be similar to those of nonsmokers. No association between cigarette smoking and levels of plasma cholesterol was observed in men and women over age 60. Possible mechanisms for this observed relationship include an antiestrogenic effect of cigarette smoking that makes the observation more noticeable in younger female cohorts, enhanced lipolysis that increases levels of plasma free fatty acids, or differences in dietary intake between smokers and nonsmokers. |
| Cigarette smoking and random serum cholesterol levels in a Northern Ireland general practice population of 18- to 20-year-old students and non-students Brown, J. S. and K. Steele (1996), Br J Gen Pract 46(412): 665-9. Abstract: BACKGROUND: Coronary heart disease is the commonest cause of death in Northern Ireland, but few data exist on the incidence of risk factors in young adult students and non-students. AIM: To gather data on the prevalence of cigarette smoking and raised serum total cholesterol in a population of 18- to 20-year-old students and non-students. METHOD: Subjects were patients are Mountsandel Surgery, Coleraine on 1 January 1989 and were 18-20 years of age inclusive on that date. Subjects were interviewed by a research nurse who recorded socio-demographic data, tobacco consumption and random serum total cholesterol. Smoking status validation was by serum thiocyanate and expired air carbonmonoxide estimations. RESULTS: Out of the 832 subjects surveyed, 570 were students and 262 were non-students. Cigarettes were smoked by 239 (28.7%) subjects, and a significantly greater proportion of non-students compared with students were smokers (36.6% and 25.1%, respectively; P < 0.001). The proportion of males compared with females who smoked cigarettes was not significantly different, but males smoked significantly more cigarettes per day than females (14 and 11 cigarettes, respectively; P = 0.005). The average age for commencing regular cigarette smoking was 15.3 years, and 49.9% of smokers had started regular smoking by the age of 16 years. A greater proportion of non-students (65.7%) compared with students (39.2%) had started smoking before the age of 16 years. Out of those sampled, 156 (19.2%) had random serum cholesterol levels above 5.2 mmol l-1. Mean total cholesterol for non-students was significantly higher than for students (4.61 and 4.45 mmol l-1, respectively; P = 0.01) and increased significantly with increasing age (P = 0.03). Three subjects recorded cholesterol levels above 7.8 mmol l-1. CONCLUSION: Cigarette smoking and raised serum total cholesterol were prevalent among an apparently healthy population of students and non-students. These young adults may be significantly more at risk from subsequent coronary heart disease than was previously suspected. |
| Cigarette smoking, high-density lipoprotein cholesterol subfractions, and lecithin: cholesterol acyltransferase in young women Imamura, H., K. Teshima, et al. (2002), Metabolism 51(10): 1313-6. Abstract: Much of the published data on the relationship of cigarette smoking (CS) with serum lipids and lipoproteins is based on studies of middle-aged individuals. Data on young women are scarce. This study examined the relationship of CS with high-density lipoprotein cholesterol (HDL-C) subfractions and lecithin:cholesterol acyltransferase (LCAT) activity in Japanese collegiate women. Twenty-three current smokers were individually matched for physical activity scores, age, and body mass index (BMI) with 23 nonsmokers. There were no significant differences between smokers and nonsmokers in the mean nutrient intakes. Smokers had significantly lower mean HDL-C, HDL2-C, total cholesterol, and LCAT activity than nonsmokers. In univariate analyses, BMI significantly negatively correlated with HDL-C and HDL2-C. LCAT activity significantly positively correlated with HDL3-C, LDL-C, total cholesterol (TC) and triglycerides (TG). In multiple regression analyses, the number of CS was positively related to TG. BMI was negatively related to TC. LCAT activity was positively related to LDL-C, TC, and TG. These results suggest that the known associations in older adults of CS with HDL-C subfractions and LCAT activity are already apparent in young women. |
| Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-alpha formation in low-density lipoprotein receptor-null mice fed high cholesterol Lee, J. H., G. T. Oh, et al. (2005), J Pharmacol Exp Ther 313(2): 502-9. Abstract: This study shows that 6-4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy-3,4-dihydro-2(1H)-quinolinone (cilostazol) suppresses the atherosclerotic lesion formation in the low-density lipoprotein receptor (Ldlr)-null mice. Ldlr-null mice fed a high cholesterol diet showed multiple plaque lesions in the proximal ascending aorta including aortic sinus, accompanied by increased macrophage accumulation with increased expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). Supplementation of cilostazol (0.2% w/w) in diet significantly decreased the plaque lesions with reduced macrophage accumulation and suppression of VCAM-1 and MCP-1 in situ. Increased superoxide and tumor necrosis factor-alpha (TNF-alpha) production were significantly lowered by cilostazol in situ as well as in cultured human umbilical vein endothelial cells (HUVECs). TNF-alpha-induced increased inhibitory kappaBalpha degradation in the cytoplasm and nuclear factor-kappaB (NF-kappaB) p65 activation in the nuclei of HUVECs were reversed by cilostazol (1 approximately 100 microM) as well as by (E)-3(4-t-butylphenyl)sulfonyl-2-propenenitrile (BAY 11-7085) (10 microM), suggesting that cilostazol strongly inhibits NF-kappaB activation and p65 translocation into the nuclei. Furthermore, in gel shift and DNA-binding assay, cilostazol inhibited NF-kappaB/DNA complex and nuclear DNA-binding activity of the NF-kappaB in the nuclear extracts of the RAW 264.7 cells. Taken together, it is suggested that the anti-atherogenic effect of cilostazol in cholesterol-fed Ldlr-null mice is ascribed to its property to suppress superoxide and TNF-alpha formation, and thereby reducing NF-kappaB activation/transcription, VCAM-1/MCP-1 expressions, and monocyte recruitments. |
| Cilostazol, a selective type III phosphodiesterase inhibitor, decreases triglyceride and increases HDL cholesterol levels by increasing lipoprotein lipase activity in rats Tani, T., K. Uehara, et al. (2000), Atherosclerosis 152(2): 299-305. Abstract: Cilostazol, a selective type III phosphodiesterase inhibitor, has antiplatelet and vasodilating effects. In this study, the effects of cilostazol on lipid metabolism and lipoprotein lipase (LPL) activity were studied in rats. Cilostazol was administered orally at doses of 30 or 100 mg/kg twice a day for 1-2 weeks to rats. Cilostazol decreased the serum triglyceride level in normolipidemic rats. The serum triglyceride level was reduced and HDL cholesterol level was increased by cilostazol in streptozotocin (STZ)-induced diabetic rats. The disappearance of exogenous triglyceride was accelerated by cilostazol in normolipidemic rats. Cilostazol increased post-heparin plasma LPL activity but had no effect on hepatic triglyceride lipase activity in STZ-induced diabetic rats. Cilostazol also increased LPL activity in the heart in STZ-induced diabetic rats. These findings suggest that an increase in LPL activity is responsible for the serum triglyceride lowering and HDL cholesterol elevating effects of cilostazol in rats. |
| Cimetidine does not alter atorvastatin pharmacokinetics or LDL-cholesterol reduction Stern, R. H., D. M. Gibson, et al. (1998), Eur J Clin Pharmacol 53(6): 475-8. Abstract: OBJECTIVE: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses were compared. RESULTS: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin with cimetidine. Mean values for Cmax (the maximum concentration) were 5.11 ng eq.ml(-1) and 4.54 ng eq.ml(-1), for tmax (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC0-24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq.h.ml(-1) and 58.5 ng eq.h.ml(-1), and for t1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change from baseline for total cholesterol were -29.5% and -29.9%, for low-density lipoprotein (LDL) cholesterol -41.0% and -42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides -33.8% and -25.8%, respectively. CONCLUSIONS: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced by coadministration of cimetidine. |
| Cinnamate supplementation enhances hepatic lipid metabolism and antioxidant defense systems in high cholesterol-fed rats Lee, J. S., S. M. Jeon, et al. (2003), J Med Food 6(3): 183-91. Abstract: This study investigated the effect of cinnamate, a phenolic compound found in cinnamon bark and other plant materials, on lipid metabolism and antioxidant enzyme activities in rats fed a high cholesterol diet. Three groups of rats were given a diet containing 1 g of cholesterol/kg for 6 weeks. The control group only received the high cholesterol diet, whereas the other two groups received a diet supplemented with lovastatin or cinnamate (0.1 g/100 g of diet). The plasma high-density lipoprotein-cholesterol levels were significantly higher in the cinnamate group than in either the control or lovastatin groups, and the atherogenic index was significantly lower in rats with cinnamate supplementation. Supplementation with cinnamate resulted in significantly lower hepatic cholesterol and triglyceride levels. Accumulation of hepatic lipid droplets was higher in the control group than in the rats supplemented with either cinnamate or lovastatin. Hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was significantly lower in the cinnamate group compared with the other groups, whereas only acyl-CoA:cholesterol acyltransferase activity was significantly lower in the lovastatin group compared with the control group. Cinnamate supplementation resulted in higher catalase and glutathione peroxidase activities, while hepatic thiobarbituric acid-reactive substances were significantly lower in both the cinnamate and lovastatin groups. The fecal acidic sterol was higher in the lovastatin group than in the control or cinnamate groups. These results suggest that dietary cinnamate inhibits hepatic HMG-CoA reductase activity, resulting in lower hepatic cholesterol content, and suppresses lipid peroxidation via enhancement of hepatic antioxidant enzyme activities. |
| Circadian changes in remnant-like particle-cholesterol (RLP-C), and its diagnostic value for postprandial increase in remnant lipoprotein in diabetes mellitus Miida, T., Y. Yamada, et al. (1998), Rinsho Byori 46(2): 133-8. Abstract: To investigate whether remnant-like particle-cholesterol (RLP-C) increases in the postprandial state, and if so, whether such response can be used for detecting postprandial increase in remnant lipoprotein, we measured RLP-C levels at two points (before breakfast, and after lunch), or seven points (before and after each meal, and midnight) in 36 diabetic patients. delta RLP-C was calculated by subtracting RLP-C level before breakfast from that at each point. delta RLP-C after lunch was defined as delta RLP-CL and maximum delta RLP-C as delta RLP-Cmax. Daily profiles of RLP-C (n = 22) showed that RLP-C increased during the daytime in 6 patients (27.3%; responders), but not in the others (nonresponders). In the histogram of delta RLP-Cmax, we could easily distinguish responders (delta RLP-Cmax = 6 approximately 12 mg/dl) from nonresponders (< 4 mg/dl). By using delta RLP-CL of 4 mg/dl as the cut-off value, we could also separate two groups without overlap. With this cut-off value, 11 out of 36 patients (30.6%) were diagnosed as responders. High performance liquid chromatography (HPLC) analysis with cholesterol-monitoring revealed that VLDL-sized RLP increased markedly after lunch in responders. In conclusion, RLP-C increases in some diabetic patients, and delta RLP-CL is useful for detecting postprandial increase in remnant lipoprotein. |