| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Cholesterol synthesis in the rat brain in course of late development as determined by 3-hydroxy-3-methylglutaryl CoA reductase activity Michalak, S. and M. Wender (1996), Folia Neuropathol 34(1): 7-10. Abstract: The activity of 3-hydroxy-3-methylglutaryl-CoA reductase (E.C. 1.1.1.88), the key regulatory enzyme in the process of cholesterol biosynthesis was evaluated in different development stages of rat brain. The obtained results have shown an almost twofold increase of HMG-CoA reductase activity in one year old rats compared to the reference 4 months old animals. The activity of the cerebral HMG-CoA reductase in two years old animals dropped to the level observed in the reference group. The enhancement of activity of the regulatory enzyme for cholesterol biosynthesis occurs in parallel with an appearance of quantitatively minor, other than cholesterol, free sterol normally absent in the brains of young animals. |
| Cholesterol synthesis in the vertebrate retina: effects of U18666A on rat retinal structure, photoreceptor membrane assembly, and sterol metabolism and composition Fliesler, S. J., M. J. Richards, et al. (2000), Lipids 35(3): 289-96. Abstract: Treatment of neonatal rats with U18666A, an inhibitor of desmosterol delta24-reductase, results in accumulation of desmosterol (delta5,24) and depletion of cholesterol (delta5) in various bodily tissues and also causes cataracts. We evaluated the effects of U18666A on the sterol composition, de novo sterol synthesis, and histological structure of the retina. Neonatal Sprague-Dawley rats were injected subcutaneously with U18666A (15 mg/kg, in olive oil) every other day from birth through 3 wk of age; in parallel, control rats received olive oil alone. At 21 d, treated and control groups each were subdivided into two groups: one group of each was injected intravitreally with 3Hacetate; retinas were removed 20 h later and nonsaponifiable lipids (NSL) were analyzed by radio-high-performance liquid chromatography. The other group was injected intravitreally with 3Hleucine; 4 d later, one eye of each animal was evaluated by light and electron microscopy and light microscopic autoradiography, while contralateral retinas and rod outer segment (ROS) membranes prepared therefrom were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis/fluorography. In the treated group, the delta5/delta5,24 mole ratio of retinas was ca. 1.0, and >88% of the NSL radioactivity was in delta5,24; in contrast, control retinas had delta5/delta5,24 >170, with >80% of the NSL radioactivity in delta5. Retinal histology, ultrastructure, ROS renewal rates, and rhodopsin synthesis and intracellular trafficking were comparable in both treated and control animals. These results suggest that desmosterol can either substitute functionally for cholesterol in the retina or it can complement subthreshold levels of cholesterol by sterol synergism. |
| Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse Clarke, G. A., G. Bouchard, et al. (2004), Gut 53(1): 136-42. Abstract: BACKGROUND AND AIMS: Newly synthesised cholesterol contributes poorly to biliary lipid secretion but may assume greater importance when the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) is upregulated. As this occurs in the gall stone susceptible C57L/J inbred mouse, we employed two cholesterol biosynthesis inhibitors, Tu 2208 and Ro 48-8071, potent inhibitors of squalene epoxidase and oxidosqualene-lanosterol cyclase, respectively, to assess their potential in preventing cholesterol cholelithiasis in the C57L/J mouse strain. Mice were fed a lithogenic diet comprising a balanced nutrient intake with 15% dairy fat, 1% cholesterol, and 0.5% cholic acid added. METHODS: We determined gall stone phenotype, HMGR activity, biliary lipid secretion rates, and counterregulatory events in male C57L/J mice and gall stone resistant AKR treated with Tu 2208 (30-60 mg/kg/day) or Ro 48-8071 (30-100 mg/kg/day), while ingesting chow or the lithogenic diet. RESULTS: Both agents reduced the gall stone prevalence rate from 73% to 17% in C57L/J mice, inhibited HMGR activity, and decreased hepatic cholesterol concentrations without appreciably influencing biliary cholesterol secretion. In C57L as well as AKR mice, both agents increased biliary phospholipid (which is mostly phosphatidylcholine) secretion rates and at the highest doses effectively reduced the biliary cholesterol saturation index. CONCLUSIONS: Cholesterol biosynthesis inhibitors acting distally to squalene do not reduce biliary cholesterol secretion rates despite reductions in cholesterol biosynthesis and hepatocellular levels. However, they effectively prevent gall stone formation through stimulation of pathways that lead to enhanced biliary phospholipid secretion. |
| Cholesterol synthesis inhibitors do not reduce Lp(a) levels in normocholesterolemic patients Pazzucconi, F., G. Franceschini, et al. (1996), Pharmacol Res 34(3-4): 131-3. Abstract: Experimental and clinical data suggest that activation of the LDL receptors by the use of HMG CoA reductase inhibitors, in the presence of normal plasma cholesterol levels, may result in a reduction of Lp(a) concentrations. This hypothesis has been tested in an open study on seven subjects with normal cholesterolemia but marked elevations of Lp(a) levels, three of whom received pravastatin and four simvastatin at standard therapeutic doses. While the two drugs caused the expected reduction of plasma total and LDL cholesterol levels, no significant changes in Lp(a) were noted. This study contradicts a prior clinical finding and suggests that HMG CoA reductase inhibitors are unlikely to reduce plasma Lp(a) levels even in the absence of hypercholesterolemia. |
| Cholesterol synthesis inhibitors in cholesterol gallstone disease Smit, J. W., K. J. VanErpecum, et al. (1996), Scand J Gastroenterol Suppl 218: 56-60. Abstract: Cholesterol synthesis inhibitors (HMG-CoA Reductase Inhibitors) are reported to decrease cholesterol saturation index of duodenal bile in hypercholesterolaemic subjects. The dissolution of gallstones in animals on treatment with these drugs created expectations of a therapeutical role for these drugs in cholesterol gallstone disease. However, in prospective studies with these drugs in humans, no effect on number and size of cholesterol gallstones was observed. This is likely the result of the fact that not just biliary secretion of cholesterol is decreased during treatment with these drugs in cholesterol gallstone disease, but phospholipids and bile salts as well. As a consequence, nucleation time of cholesterol crystals in gallbladder bile is not influenced by these drugs. Another important determinant in cholesterol gallstone disease, e.g. gallbladder motility, is not influenced by HMG-CoA reductase inhibitors. Although these drugs and their metabolites are secreted into the bile, they do not influence biliary lithogenicity. In conclusion, there seems to be no therapeutic role for HMG-CoA reductase inhibitors in the treatment of cholesterol gallstone disease, although no negative effects on determinants of cholesterol gallstone formation during treatment with these drugs are observed either. |
| Cholesterol synthesis inhibitors. Clinical studies on lowering coronary risk and plaque stabilization Muller-Wieland, D., M. Faust, et al. (1998), Internist (Berl) 39(9): 934-42. |
| Cholesterol synthesis is down-regulated during regeneration of peripheral nerve Goodrum, J. F. (1990), J Neurochem 54(5): 1709-15. Abstract: The discovery of apolipoprotein E synthesis and secretion by injured peripheral nerve to the hypothesis that endoneurial apolipoprotein E serves to salvage degenerating myelin cholesterol. This salvaged cholesterol could then be reutilized by Schwann cells during remyelination via uptake through low-density lipoprotein receptors. As a test of this hypothesis, we measured the rate of cholesterol synthesis in rat sciatic nerve endoneurium during development and at various times following a crush injury at 50 days of age. In control nerves 14Cacetate incorporation into cholesterol and 3-hydroxy-3-methylglutaryl-CoA reductase activity were closely linked throughout development, indicating that reductase activity in nerve, as in other tissues, is a good indicator of cholesterol's synthetic rate. In the crushed nerves cholesterol synthesis fell to nearly zero during the first week after the crush. There was a partial recovery during the second to fourth weeks, but unlike that of other lipids, cholesterol synthesis remained well below control nerve values throughout most of the 15-week post-crush period examined. Thus, cholesterol synthesis is at very low levels during the myelination of regenerating axons. These results are consistent with a receptor-mediated down-regulation of cholesterol synthesis by lipoproteins, and would be expected if Schwann cells were utilizing an external source of cholesterol as postulated above. |
| Cholesterol synthesis is increased in mixed hyperlipidaemia Naoumova, R. P., K. D. Kim, et al. (1998), Biochim Biophys Acta 1394(2-3): 146-52. Abstract: We showed previously that hypertriglyceridaemia, but not hypercholesterolaemia, is correlated with increases in cholesterol synthesis and apolipoprotein B secretion in patients with secondary hypertriglyceridaemia. The aim of the present study was to compare the rate of cholesterol synthesis, using fasting plasma mevalonic acid (MVA) as an index, in patients with primary mixed hyperlipidaemia (type IIb phenotype, n=45) and primary hypercholesterolaemia (type IIa phenotype, n=92). LDL cholesterol was significantly higher in types IIa (6.38+/-0.18 mmol/l) and IIb (5.89+/-0.25 mmol/l) compared to 40 normolipidaemic controls (2. 99+/-0.1 mmol/l, P<0.0001), whereas serum triglyceride was higher in type IIb (2.62 (range 2.2-3.0) mmol/l) than type IIa (1.22 (range 0. 85-1.60) mmol/l, P<0.001) and controls (0.90 (range 0.68-1.24) mmol/l, P<0.001). Similarly, MVA was higher in type IIb (7.0+/-0.46 ng/ml) than IIa (5.6+/-0.23 ng/ml, P<0.0) and controls (5.6+/-0.36 ng/ml, P<0.05). Plasma MVA correlated positively with serum triglyceride (r=0.22, P=0.004) and negatively with LDL cholesterol (r=-0.21, P=0.014). These results are in accordance with previous observations that VLDL-apolipoprotein B secretion and cholesterol synthesis are linked and demonstrate that the latter is increased in mixed hyperlipidaemia. |
| Cholesterol synthesis is required for cutaneous barrier function in mice Feingold, K. R., M. Q. Man, et al. (1990), J Clin Invest 86(5): 1738-45. Abstract: Previous studies have shown that topical acetone treatment results in the removal of stratum corneum lipids and disruption of the permeability barrier. This disruption stimulates epidermal lipid synthesis which is associated with the rapid restoration of stratum corneum lipids and barrier function. The aim of this study was to determine the role of cutaneous cholesterol synthesis in the barrier recovery. Here we show that topical lovastatin, a competitive inhibitor of HMG CoA reductase, inhibits cholesterol synthesis. After acetone disruption of the barrier, the normal rapid return of cholesterol to the stratum corneum and recovery of barrier function is impaired in animals treated topically with lovastatin. When lovastatin animals are simultaneously treated topically with either mevalonate, the immediate product of HMG CoA reductase, or cholesterol, the final end product of the pathway, the recovery of the barrier is normalized. Lovastatin resulted in the delayed secretion and abnormal appearance of lamellar bodies. These results provide the first evidence demonstrating that cholesterol synthesis is required for the maintenance of barrier structure and function and suggests a crucial role for cholesterol synthesis in allowing for terrestrial existence. |
| Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts Zhuang, L., J. Kim, et al. (2005), J Clin Invest 115(4): 959-68. Abstract: Lipid rafts are cholesterol- and sphingolipid-enriched microdomains in cell membranes that regulate phosphorylation cascades originating from membrane-bound proteins. In this study, we tested whether alteration of the cholesterol content of lipid rafts in prostate cancer (PCa) cell membranes affects cell survival mechanisms in vitro and in vivo. Simvastatin, a cholesterol synthesis inhibitor, lowered raft cholesterol content, inhibited Akt1 serine-threonine kinase (protein kinase Balpha)/protein kinase B (Akt/PKB) pathway signaling, and induced apoptosis in caveolin- and PTEN-negative LNCaP PCa cells. Replenishing cell membranes with cholesterol reversed these inhibitory and apoptotic effects. Cholesterol also potentiated Akt activation in normal prostate epithelial cells, which were resistant to the apoptotic effects of simvastatin. Elevation of circulating cholesterol in SCID mice increased the cholesterol content and the extent of protein tyrosine phosphorylation in lipid rafts isolated from LNCaP/sHB xenograft tumors. Cholesterol elevation also promoted tumor growth, increased phosphorylation of Akt, and reduced apoptosis in the xenografts. Our results implicate membrane cholesterol in Akt signaling in both normal and malignant cells and provide evidence that PCa cells can become dependent on a cholesterol-regulated Akt pathway for cell survival. |
| Cholesterol test is recommended to all Americans older than 20 years Carlson, L. A. (2001), Lakartidningen 98(42): 4568-70, 4573. |
| Cholesterol testing Ellin, M. J. (1990), Md Med J 39(7): 692. |
| Cholesterol testing Maganzini, H. C. (1990), Md Med J 39(1): 41-6. |
| Cholesterol testing and management: a national comparison of family physicians, general internists, and cardiologists Eaton, C. B., A. Monroe, et al. (1998), J Am Board Fam Pract 11(3): 180-6. Abstract: BACKGROUND: We wanted to compare the frequency of cholesterol testing and treatment of hypercholesterolemia in patients cared for by family physicians, general internists, and cardiologists. METHODS: This study was a continuous cross-sectional survey of 1991 ambulatory office visits using a national probability sample of US physicians' office practices (National Ambulatory Care Survey). The physicians surveyed self-reported their specialty as family practice, internal medicine, or cardiology. Records of 33,795 patient visits to 1354 physicians were reviewed to find out whether the physicians reported cholesterol testing, cholesterol counseling, and charting of patient use of lipid-lowering medications. The results were compared among the three specialist groups. RESULTS: During an annual health examination (9.77 million office visits), a cholesterol test was reported by 23.5 percent of family physicians, 43.5 percent of internists, and 13.1 percent of cardiologists (P < 0.01). For all hypercholesterolemic patients (23.52 million office visits), the age- and sex-adjusted percentages of reported cholesterol-reduction counseling during office visits were 38.3 percent for family physicians, 42.4 percent for internists, and 36.5 percent by cardiologists (NS), and percentages of reported lipid-lowering medication prescriptions were 13.4 percent for family physicians, 25.1 percent for internists, and 28.4 percent for cardiologists (P < 0.01). In hypercholesterolemic patients with coronary heart disease (3.47 million office visits), the age- and sex-adjusted percentages of cholesterol reduction counseling reported during office visits were 64.4 percent for family physicians, 47.1 percent for internists, and 35.9 percent for cardiologists (NS) and the age- and sex-adjusted percentages of lipid-lowering medication prescriptions reported were 13.9 percent for family physicians, 62.5 percent for internists, and 34.7 percent for cardiologists (P < 0.01). CONCLUSIONS: Recommended goals regarding cholesterol testing and management were not reached by any physician group. Internists tested for hypercholesterolemia during an annual health examination more frequently and had more patients using lipid-lowering medications than did family physicians or cardiologists. Understanding the reasons for these specialty differences might lead to improvement in the diagnosis and management of hypercholesterolemia and therefore reduction in cardiovascular disease. |
| Cholesterol testing and standardization Cooper, G. R. and G. L. Myers (1991), J Med Assoc Ga 80(2): 81-4. |
| Cholesterol testing in a department store Carlson, L. A., B. Elving, et al. (1999), Lakartidningen 96(5): 448. |
| Cholesterol testing in young adults. Prudent or profligate? Naylor, C. D. (1993), Jama 269(11): 1426-7. |
| Cholesterol testing with desk-top machines Sharp, I. and M. Rayner (1990), Lancet 335(8680): 55. |
| Cholesterol testing. The Australasian Epidemiological Association Jamrozik, K. D. (1991), Med J Aust 155(7): 495. |
| Cholesterol testing--a lifestyle focus for the nineties Seccombe, D. W. (1993), Clin Biochem 26(1): 17-9. |