| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Long-term prognostic importance of total cholesterol in elderly survivors of an acute myocardial infarction: the Cooperative Cardiovascular Pilot Project Foody, J. M., Y. Wang, et al. (2003), J Am Geriatr Soc 51(7): 930-6. Abstract: OBJECTIVES: To determine the long-term prognostic importance of in-hospital total serum cholesterol in elderly survivors of acute myocardial infarction (AMI). DESIGN: Retrospective medical record review. SETTING: Acute care, nongovernmental hospitals in Alabama, Connecticut, Iowa, and Wisconsin. PARTICIPANTS: Four thousand nine hundred twenty-three Medicare beneficiaries from four states aged 65 and older discharged alive with a principal diagnosis of AMI between June 1, 1992, and February 28, 1993, who had a measurement of total serum cholesterol during hospitalization. MEASUREMENTS: Primary endpoint of all-cause mortality within 6 years of discharge. RESULTS: Of the 7,166 hospitalizations meeting study inclusion criteria, 4,923 (68.7%) had total cholesterol assessed, and 22% had a cholesterol level of 240 mg/dL or greater. Of AMI hospitalization survivors with cholesterol of 240 md/dL or greater, 17.2% died within 1 year and 47.9% died within 6 years, compared with 17.4% (P =.73) and 48.7% (P =.98) of those with a cholesterol level less than 240 mg/dL. The adjusted hazard ratio for elevated total serum cholesterol measured during hospitalization for all-cause mortality in the 6 years after discharge was 0.97 (95% confidence interval (CI) = 0.87-1.09). The unadjusted 1- and 6-year mortality rates for those with total cholesterol less than 160 mg/dL were 22.2% and 55.5%, respectively, not significantly different from mortality for patients with cholesterol of 160 mg/dL or greater, even after adjustment. CONCLUSION: Among elderly survivors of AMI, elevated total serum cholesterol measured postinfarction is not associated with an increased risk of all-cause mortality in the 6 years after discharge. Furthermore, this study found no evidence of an increased risk of all-cause mortality in patients with low total cholesterol. Further studies are needed to determine the relationship of postinfarction lipid subfractions and mortality in older patients with coronary artery disease (CAD). |
| Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC) Obarzanek, E., S. Y. Kimm, et al. (2001), Pediatrics 107(2): 256-64. Abstract: OBJECTIVE: Diets reduced in fat and cholesterol are recommended for children over 2 years of age, yet long-term safety and efficacy are unknown. This study tests the long-term efficacy and safety of a cholesterol-lowering dietary intervention in children. METHODS: Six hundred sixty-three children 8 to 10 years of age with elevated low-density lipoprotein cholesterol (LDL-C) were randomized to a dietary intervention or usual care group, with a mean of 7.4 years' follow-up. The dietary behavioral intervention promoted adherence to a diet with 28% of energy from total fat, <8% from saturated fat, up to 9% from polyunsaturated fat, and <75 mg/1000 kcal cholesterol per day. Serum LDL-C, height, and serum ferritin were primary efficacy and safety outcomes. RESULTS: Reductions in dietary total fat, saturated fat, and cholesterol were greater in the intervention than in the usual care group throughout the intervention period. At 1 year, 3 years, and at the last visit, the intervention compared with the usual care group had 4.8 mg/dL (13 mmol/L), 3.3 mg/dL (09 mmol/L), and 2.0 mg/dL (05 mmol/L) lower LDL-C, respectively. There were no differences at any data collection point in height or serum ferritin or any differences in an adverse direction in red blood cell folate, serum retinol and zinc, sexual maturation, or body mass index. CONCLUSION: Dietary fat modification can be achieved and safely sustained in actively growing children with elevated LDL-C, and elevated LDL-C levels can be improved significantly up to 3 years. Changes in the usual care group's diet suggest that pediatric practices and societal and environmental forces are having positive public health effects on dietary behavior during adolescence. |
| Long-term supplementation with a high cholesterol diet decreases the release of ATP from the caudal artery in aged rats Hashimoto, M., K. Shinozuka, et al. (1998), Life Sci 63(21): 1879-85. Abstract: We examined the effects of high cholesterol (HC) diet on the spontaneous and noradrenaline-induced release of ATP, ADP, AMP and adenosine from caudal arteries and on the plasma levels of these adenyl purines in aged (100-week-old) Wistar rats. Administration of this diet for 12 weeks significantly reduced spontaneous and noradrenaline (1 micromol/L)-evoked release of adenyl purines from the caudal arteries relative to rats given the control diet The unsaturation index of fatty acids (UI), which gives the average number of double bonds, of both the plasma and the caudal artery was significantly less in the HC diet-fed rats than in those fed the control diet. The HC diet for 12 weeks produced a slight but significant increase in systolic and diastolic blood pressure with advancing age. Regression analysis revealed a significant inverse relationship between the total amount of purines released from the artery and diastolic blood pressure, and also a positive relationship between the total amount of purines released and the UI of the caudal artery. These results suggest that the high cholesterol diet decreased the release of adenyl purines from the caudal arteries of aged rats, leading to an increase in blood pressure. |
| Long-term time-related predictivity of coronary events as a function of a single measurement of serum cholesterol and systolic blood pressure Menotti, A., M. Lanti, et al. (2000), Acta Cardiol 55(2): 87-93. Abstract: OBJECTIVE: To study the time-related association of a single measurement of serum cholesterol and systolic blood pressure with the occurrence of a first coronary event in a population sample of middle-aged men. METHODS AND RESULTS: A single measurement of serum total cholesterol and systolic blood pressure (along with age, cigarette consumption, physical activity at work and body mass index as possible confounders) was made in 1,605 coronary disease-free men aged 40-59 belonging to the Italian rural cohorts of the Seven Countries Study. During 25 years of follow-up 353 men developed a first event, that is a coronary death (sudden or not), and definite or possible myocardial infarction. Twenty-five partitioned proportional hazards models were solved, one for each independent year of follow-up, to predict the risk of incident events. Single-year hazard functions, separately for serum cholesterol and systolic blood pressure, were cumulated and smoothed. The resulting curves showed a regularly increasing risk for coronary events. They fit straight lines, with large correlation coefficients for both serum total cholesterol (r = 0.99) and systolic blood pressure (r = 0.99). These slopes were similar to the coefficients estimated by a single proportional hazards model solved for all events during 25 years. CONCLUSION: A single measurement of serum total cholesterol and systolic blood pressure in middle aged-men maintains a regular and monotonic relationship with occurrence of a first coronary event during 25 years of follow-up. |
| Long-term treatment of neonatal aortic smooth muscle cells with beta VLDL induces cholesterol accumulation Schreiber, B. M., H. V. Jones, et al. (1992), Atherosclerosis 95(2-3): 201-10. Abstract: A model for smooth muscle derived foam cells was developed by treating smooth muscle cells isolated from the aortae of neonatal rabbits with beta VLDL for up to 1 month. Hyperlipidemic beta VLDL isolated from cholesterol fed rabbits induced proliferation of the cells that were maintained in lipid deficient serum. In addition, the lipoprotein fraction stimulated 14Coleic acid incorporation into 14Ccholesteryl ester, even in cultures that had been chronically exposed to the lipoprotein. The accumulation of cholesterol was evaluated and small amounts of cholesteryl ester were demonstrated in cultures treated for 3 days with beta VLDL. However, continued exposure to the lipoprotein resulted in larger elevations in total cholesterol, approximately 65% of which was in the esterified form in cultures treated with 100 micrograms beta VLDL/ml for 24 days. When cholesterol levels were examined as a function of time, it was determined that both total cholesterol and cholesteryl ester levels increased. Approximately 2-3 weeks after lipoprotein was introduced to the culture, maximum levels were attained. Triglyceride levels were also measured and found to increase more than two-fold in cultures that had been incubated in the presence of beta VLDL for 24 days, when compared to cultures incubated in its absence. Examination of the cultures by electron microscopy revealed intracytoplasmic lipid droplets in beta VLDL treated cells. These results suggest that beta VLDL treatment of neonatal aortic smooth muscle cells provides an ideal model in which to study the lipid laden smooth muscle cells that characterize the atherosclerotic plaque. |
| Look into your cholesterol Shanmugam, S. (1994), J Assoc Physicians India 42(4): 348-9. |
| Look into your cholesterol Thakur, U. N. (1994), J Assoc Physicians India 42(9): 756. |
| Lopinavir/ritonavir combination and total/HDL cholesterol ratio Valerio, L., E. Fontas, et al. (2005), J Infect 50(3): 229-35. Abstract: OBJECTIVES: To describe the evolution of the lipidic profile among LPV/r treated patients in a 'real life' situation. METHODS: Lipids measurements at LPV/r initiation time and every 3 months, and pharmacological measurements at M3 and M6 were collected retrospectively in 142 patients attending our clinic. Dyslipidaemia was defined as total cholesterol > or =6.2 mmol/l, HDL-cholesterol > or =1 mmol/l, total/HDL-cholesterol ratio > or =6.5 and triglycerides > or =2.3 mmol/l. RESULTS: Eighty-nine percent of patients had previously received a regimen with protease inhibitors, 4% were treatment naive. At baseline, 17% of patients had high total cholesterol, 49% high triglycerides, 63% low HDL-cholesterol, 25% a high total/HDL-cholesterol ratio. At M12, the mean HDL-cholesterol increase per patient was 21%. Lipids levels significantly increased over the study period, as early as the 3rd month (6th month for ratio) and continuously until the 12th month. Among the patients with available LPV/r plasma determinations at M3, a higher lopinavir residual concentration was observed in those with high triglycerides (6.78 vs 3.02 mg/l, p = 0.05) as, at M6, in those with an elevated ratio (9.19 vs 0.96 mg/l, p = 0.02). CONCLUSIONS: Those results suggest that LPV/r may induce a significant rise in the total/HDL-cholesterol ratio, despite an increase in HDL-cholesterol levels. The association between triglycerides and total/HDL-cholesterol ratio elevated levels and high residual concentrations of lopinavir may also argue for systematic drug monitoring. |
| Loss of pacing-induced preconditioning in rat hearts: role of nitric oxide and cholesterol-enriched diet Ferdinandy, P., Z. Szilvassy, et al. (1997), J Mol Cell Cardiol 29(12): 3321-33. Abstract: We examined whether the inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine (lNNA) abolished pacing-induced preconditioning, and if prolonged exposure to cholesterol-enriched diet led to the loss of preconditioning due to decreased cardiac NO formation. Therefore, Wistar rats fed 2% cholesterol-enriched diet or standard diet for 24 weeks were treated with a single dose of 1 mg/kg lNNA or its solvent at the end of the week 24, respectively. Isolated hearts from all groups were subjected to either preconditioning induced by three consecutive periods of pacing at 600 beats/min for 5 min, with 5-min interpacing periods, or time-matched non-preconditioning perfusion, followed by a 10-min coronary occlusion, respectively. In the control group, coronary occlusion after a non-preconditioning protocol decreased aortic flow (AF) from 45.4+/-2.4 to 15.6+/-1.5 ml/min, and resulted in a lactate dehydrogenase (LDH) release of 219+/-55 mU/min/g, however, preconditioning attenuated the consequences of coronary occlusion AF: 27.3+/-1.7 ml/min (P<0.05); LDH: 44+/-14 mU/min/g (P<0.05). Preconditioning did not confer protection in the lNNA-treated (AF: 17.4+/-1.5 ml/min; LDH: 151+/-21 mU/min/g), and/or in the high-cholesterol-fed groups (AF: 15.7+/-1.2 ml/min; LDH: 168+/-22 mU/min/g). Preconditioning was preserved however, when hearts were treated with lNNA after the preconditioning protocol AF: 29.6+/-2.2 ml/min (P<0.05); LDH: 48+/-17 mU/min/g (P<0.05). Both lNNA treatment and cholesterol-enriched diet markedly decreased cardiac NO content assayed by electron spin resonance spectroscopy. We conclude that NO may be involved in the triggering mechanism of pacing-induced preconditioning, the protective effect of which is blocked by sustained exposure to dietary cholesterol, possibly by influencing cardiac metabolism of NO. |
| Loss of phosphoserine polar group asymmetry and inhibition of cholesterol transport in Jurkat cells treated with cholesterylphosphoserine Cusinato, F., W. Habeler, et al. (1998), J Lipid Res 39(9): 1844-51. Abstract: Cholesterylphosphoserine (CPHS) is a synthetic ester of cholesterol showing immunosuppressive activity. In the present study, we have used the T cell line Jurkat to investigate its mechanism of action. CPHS incorporates into cells reaching a molar ratio of 0.23 and 3.9 with the total phospholipid and cholesterol content, without inducing necrosis or apoptosis. CPHS incorporation elicits a dose-dependent binding of fluorescein isothiocyanate-labeled annexin V, suggesting that the steroid distributes in the external leaflet of plasma membrane exposing the phosphoserine group to the external cell environment and inserting the steroid ring into the phospholipid bilayer. In agreement with a preferential steroid association with sphingolipids, CPHS is included in a Triton X-100-insoluble complex when mixed with sphingomyelin and cholesterol. CPHS incorporation inhibits the esterification of low density lipoprotein (LDL)-derived cholesterol, producing a minor influence on the endogenous synthesis of cholesterol and on the acyl-CoA:cholesterol acyltransferase activity. In this effect, CPHS is as potent as progesterone (IC50 of 3.5 microM). It is concluded that the insertion of cholesterylphosphoserine (CPHS) in the Jurkat plasma membrane neutralizes the asymmetric distribution of the phosphoserine group and inhibits the movement of cholesterol to the endoplasmic reticulum. As CPHS is a negatively charged steroid, this last effect may be linked to the perturbation of sphingolipid/cholesterol-based microdomains, proposed to play a role in cholesterol trafficking. |
| Loss of resistance to dietary cholesterol in the rat after hypophysectomy: importance of the presence of growth hormone for hepatic low density lipoprotein-receptor expression Rudling, M. and B. Angelin (1993), Proc Natl Acad Sci U S A 90(19): 8851-5. Abstract: This investigation was undertaken to determine the role of pituitary function and, in particular, the possible influence of growth hormone (GH) on hepatic low density lipoprotein (LDL)-receptor expression in response to dietary cholesterol. Feeding normal rats with 2% cholesterol for 5 or 6 days did not alter LDL-receptor numbers, LDL-receptor mRNA levels, or plasma cholesterol, although hepatic cholesterol increased 5-fold. When hypophysectomized rats received the same diet, the LDL-receptor number and its mRNA levels were reduced by 75%, plasma cholesterol increased 6-fold, and hepatic cholesterol increased 12-fold. Stepwise hormonal substitution of cholesterol-fed, hypophysectomized rats revealed that substitution with GH was important to restore hepatic LDL-receptor number and mRNA levels. The presence of GH was also important to reduce the hypercholesterolemia in cholesterol-fed hypophysectomized rats. We conclude that the presence of GH is important for hepatic LDL-receptor expression, both at the protein and the mRNA level. The resistance to suppression of rat hepatic LDL receptors by dietary cholesterol depends, at least in part, on the presence of GH. |
| Lovastatin added to ursodeoxycholic acid further reduces biliary cholesterol saturation Logan, G. M. and W. C. Duane (1990), Gastroenterology 98(6): 1572-6. Abstract: The effects of lovastatin and ursodeoxycholic acid on cholesterol saturation of gallbladder bile were examined, alone and in combination. Nine volunteers were studied before any treatment and after each of three treatment periods: lovastatin, 40 mg, twice a day; ursodeoxycholic acid, 10 mg/kg per day; and the combination of both drugs. Treatment periods were randomly ordered, lasted 4-5 wk, and each was preceded by a 3-wk washout period. Mean cholesterol saturation index decreased from a baseline value of 1.40-0.92 on lovastatin (p less than 0.008). Mean cholesterol saturation index on ursodeoxycholic acid was 0.87 and decreased to 0.70 with the addition of lovastatin (p less than 0.030). There was a strong correlation (r = 0.87, p less than 0.003) between saturation index on ursodeoxycholic acid and the further incremental reduction in saturation index with addition of lovastatin. These findings raise the possibility that addition of lovastatin to ursodeoxycholic acid treatment might improve the efficacy of this bile salt for dissolution of cholesterol gallstones, especially in patients with a suboptimal response to ursodeoxycholic acid. |
| Lovastatin and simvastatin--inhibitors of HMG CoA reductase and cholesterol biosynthesis Alberts, A. W. (1990), Cardiology 77 Suppl 4: 14-21. Abstract: The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is a key rate-controlling step early in the cholesterol biosynthetic pathway that catalyzes the conversion of HMG CoA to mevalonic acid. Since this enzyme plays a significant role in regulating cholesterol synthesis, it is a rational target for pharmacologic intervention. The first potent, specific inhibitor of HMG CoA was mevastatin (compactin, ML-236B), which was discovered in 1976 by Endo et al. J Antibiot 1976:29:1346-1348. Subsequently, lovastatin, a novel, more active fungal metabolite was isolated from a strain of Aspergillus terreus. Lovastatin, the first of this class of agents to be approved for clinical use, was chemically modified to form simvastatin. Simvastatin is superior to lovastatin in intrinsic inhibitory potency. Both are inactive lactone prodrugs that must be converted to their respective dihydroxy open-acid forms to elicit inhibitory activity. Pharmacologic characterization of lovastatin and simvastatin has demonstrated that these potent inhibitors of HMG CoA reductase specifically inhibit cholesterol synthesis in animal cells, as well as in vivo after oral administration of the agents. Oral administration of either lovastatin or simvastatin to dogs in the presence or absence of the bile acid sequestrant cholestyramine results in a marked, sustained lowering of plasma cholesterol. Associated with the cholesterol lowering is a decrease in urinary and plasma levels of mevalonic acid, the end product of the HMG CoA reductase reaction. The target organ for inhibitors of HMG CoA reductase is the liver, the primary site of cholesterol biosynthesis. Both lovastatin and simvastatin are preferentially extracted by this organ.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Lovastatin decreases de novo cholesterol synthesis and LDL Apo B-100 production rates in combined-hyperlipidemic males Cuchel, M., E. J. Schaefer, et al. (1997), Arterioscler Thromb Vasc Biol 17(10): 1910-7. Abstract: The effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, on the kinetics of de novo cholesterol synthesis and apolipoprotein (apo) B in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) was investigated in five male patients with combined hyperlipidemia. Subjects were counseled to follow a Step 2 diet and were treated with lovastatin and placebo in randomly assigned order for 6-week periods. At the end of each experimental period, subjects were given deuterium oxide orally and de novo cholesterol synthesis was assessed from deuterium incorporation into cholesterol and expressed as fractional synthesis rate (C-FSR) and production rate (C-PR). Simultaneously, the kinetics of VLDL, IDL, and LDL apo B-100 were studied in the fed state using a primed-constant infusion of deuterated leucine to measure fractional catabolic rates (FCR) and production rates (PR). Drug treatment resulted in significant decreases in total cholesterol (-29%), VLDL cholesterol (-40%), LDL cholesterol (-27%), and apo B (-16%) levels and increases in HDL cholesterol (+13%) and apolipoprotein (apo) A-I (+11%) levels. Associated with these plasma lipoprotein responses was a significant reduction in both de novo C-FSR (-40%; P =.04) and C-PR (-42%; P =.03). Treatment with lovastain in these patients had no significant effect on the FCR of apoB-100 in VLDL, IDL, or LDL, but resulted in a significant decrease in the PR of apoB-100 in IDL and LDL. Comparing the kinetic data of these patients with those of 10 normolipidemic control subjects indicates that lovastatin treatment normalized apoB-100 IDL and LDL PR. The results of these studies suggest that the declines in plasma lipid levels observed after treatment of combined hyperlipidemic patients with lovastatin are attributable to reductions in the C-FSR and C-PR of de novo cholesterol synthesis and the PR of apoB-100 containing lipoproteins. The decline in de novo cholesterol synthesis, rather than an increase in direct uptake of VLDL and IDL, may have contributed to the decline in the PR observed. |
| Lovastatin decreases plasma and platelet cholesterol levels and normalizes elevated platelet fluidity and aggregation in hypercholesterolemic patients Hochgraf, E., Y. Levy, et al. (1994), Metabolism 43(1): 11-7. Abstract: The lipid composition of whole platelets and the fluidity of platelet membranes, as well as the sensitivity of the cell to aggregation, were studied in type IIA hypercholesterolemic human subjects before and after treatment with lovastatin. Fourteen patients with primary hypercholesterolemia having initial cholesterol levels of 383 +/- 52 mg/dL (mean +/- standard deviation) were studied and compared with 21 control subjects having cholesterol levels of 187 +/- 32 mg/dL. Lovastatin was administered orally at a starting dose of 40 mg daily. The dose was increased to 80 mg daily for eight patients who did not achieve the target cholesterol level of 200 mg/dL at 6 weeks. Serum cholesterol level was decreased by 37% following 20 weeks' administration of the drug. The fluidity of platelet membranes expressed in terms of the fluorescence anisotropy parameter was determined using the probe 1,6-diphenyl-1,3,5-hexatriene (DPH). When compared with platelets obtained from normocholesterolemic controls, platelets from hypercholesterolemic patients had a higher molar ratio of cholesterol to phospholipids (C/PL 0.86 +/- 0.15 v 0.57 +/- 0.06 for controls) and of phosphatidylcholine to sphingomyelin (PC/SM 2.64 +/- 0.87 v 2.00 +/- 0.15 for controls), enhanced fluidity (anisotropy parameter at 37 degrees C of 0.892 +/- 0.066 v 0.977 +/- 0.065 for controls), and a greater tendency to aggregate (aggregation of 84.2% +/- 6.3% v 78.5% +/- 7.6% for controls).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Lovastatin efficacy in reducing low-density lipoprotein cholesterol levels on high- vs low-fat diets Cobb, M. M., H. S. Teitelbaum, et al. (1991), Jama 265(8): 997-1001. Abstract: The effectiveness of lovastatin was compared with both a high-fat vs low-fat diet. Hypercholesterolemic subjects were studied under metabolic ward conditions for diet periods of 3 weeks while receiving lovastatin (40 mg/d) or placebo. Multiple lipoprotein levels were measured during the final week of each diet period. Nineteen subjects completed the study on the high-fat (43% of kilojoules) diet and 16 on the low-fat (25% of kilojoules) diet. Lovastatin reduced total cholesterol by 23% and low-density lipoprotein cholesterol by 30%, compared with placebo on both diets, with no significant diet-drug interaction. High-density lipoprotein cholesterol was raised by 7% to 8% on the diet regimens. Addition of lovastatin to the low-fat diet permitted 80% of subjects on this diet, but less than 50% of those on the high-fat diet, to achieve current guidelines. Although lovastatin produces a comparable percentage reduction in lipoprotein profiles on either diet, the accompanying low-fat diet remains advisable for additional reduction of low-density lipoprotein cholesterol levels to specified goals. |
| Lovastatin enhances the photocytotoxicity of UVA radiation towards cultured N.C.T.C. 2544 human keratinocytes: prevention by cholesterol supplementation and by a cathepsin inhibitor Quiec, D., C. Maziere, et al. (1995), Biochem J 310 (Pt 1): 305-9. Abstract: The effect of the hydroxymethylglutaryl-CoA (HMG-CoA) inhibitor lovastatin on the UVA-induced photocytotoxicity has been investigated in cultured human N.C.T.C. 2544 keratinocytes. In the absence of irradiation, 5 x 10(-7) M lovastatin did not exhibit any significant cytotoxic effect towards this cell line. Although the drug cannot act as a photosensitizer, because it does not absorb in the UVA range, it markedly increased the UVA-induced cellular damage (about 70% reduction in cell viability at 5 x 10(-7) M). This effect was not accompanied by an increase in the lipid peroxidation product content of cells as compared with treatment with UVA alone. Medium supplementation with 0.01 mg/ml free cholesterol totally prevented the enhancement of UVA photocytotoxicity induced by lovastatin. A protective effect was also observed when cells were supplemented with an amount of low-density lipoprotein giving the same cholesterol concentration in the culture medium. Finally, E64 L-trans-epoxysuccinyl-leucylamido-(4-guanidino)-butane, a lysosomal cathepsin inhibitor, also prevents the cell death induced by UVA in cells treated with lovastatin. These results suggest that HMG-CoA reductase inhibitors could increase the sensitivity of skin cells to UVA radiation, and that this phenomenon is related to lysosomal enzyme release. |
| Lovastatin induces synthesis of cholesterol, which acts as a secretagogue of biliary phospholipids in rats Linscheer, W. G., B. Atreyee, et al. (1995), Am J Physiol 268(2 Pt 1): G242-50. Abstract: The effects of treatment with lovastatin (LS), a hypocholesterolemic drug, on hepatic metabolism of cholesterol (CH) and phosphatidylcholine (PC) were studied in rats. Hepatic synthesis of CH was increased, as previously reported by our laboratory. Total plasma CH was increased, and biliary secretion of CH was raised fourfold, but biliary secretion of bile salts was not affected. Because CH is practically insoluble in an aqueous milieu, we tested the hypothesis that excessive CH is solubilized and secreted into bile as cholesterol-phospholipid (CH-PL) vesicles. The effects of LS-induced increase in CH synthesis on hepatic metabolism of PC after 7 days of oral LS treatment (17.5 mg/day) were studied. Our results showed accelerated synthesis of PC and increased biliary secretion of newly formed PC into bile, as evidenced by the following. 1) Phosphocholine cytidylyltransferase (EC 2.7.7.15) activity, the rate limiting enzyme in the synthesis of PC, increased 2.5-fold in the hepatic microsomes of the hepatocytes. 2) After intravenous administration of 14Ccholine, a precursor of PC, 14CPC increased significantly in bile. 3) Biliary output of PC increased twofold. 4) Quasi-elastic light scattering measurements of bile showed a 3.5-fold increase in intensity of the CH-PL vesicles, indicating higher concentrations of CH-PL vesicles, but there was no change in the intensity of the micelles. These observations support the hypothesis that PC synthesis was enhanced as a transport mechanism for secretion of the excessive amounts of cholesterol from the hepatocytes into bile as CH-PC vesicles. |
| Lovastatin inhibits gallstone formation in the cholesterol-fed prairie dog Saunders, K. D., J. A. Cates, et al. (1991), Ann Surg 214(2): 149-54. Abstract: The efficacy of lovastatin, an inhibitor of hepatic cholesterol synthesis in the prevention of cholesterol gallstone formation, was evaluated in the prairie dog model. Two groups of animals were maintained on either nonlithogenic or 1.2% cholesterol-enriched chow for 21 days. Seven of the animals in each group received lovastatin, and the remaining six received only distilled water. All of the cholesterol-fed/water-treated animals had crystals and 83% had gallstones, but none of the cholesterol-fed/lovastatin-treated animals had gallstones and only three had microscopic crystals. These data indicate that lovastatin inhibits cholesterol gallstone formation in a diet-induced model of gallstone disease. |
| Lovastatin inhibits HIV-1 expression in H9 human T lymphocytes cultured in cholesterol-poor medium Maziere, J. C., J. C. Landureau, et al. (1994), Biomed Pharmacother 48(2): 63-7. Abstract: The effects of the HMG-Coenzyme A reductase inhibitor lovastatin on HIV-1 expression and sterol synthesis have been investigated in the human H9 lymphocytic cell line. To this purpose, sterol synthesis from 14C-acetate, cell multiplication and reverse transcriptase activity have been measured in parallel at various times after cell infection by HIV-1. It was found that nine days after viral loading, lovastatin inhibited both sterol synthesis and viral multiplication as assessed by the reverse transcriptase activity. Since HIV infection has been shown to induce alterations in membrane cholesterol content, suggesting that the virus cycle may be partially dependent upon cellular cholesterol, inhibitors of cholesterol synthesis could be an interesting way of research in order to slower HIV propagation. |