| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The peroxisome proliferator perfluorodecanoic acid inhibits the peripheral-type benzodiazepine receptor (PBR) expression and hormone-stimulated mitochondrial cholesterol transport and steroid formation in Leydig cells Boujrad, N., B. Vidic, et al. (2000), Endocrinology 141(9): 3137-48. Abstract: The peroxisome proliferator perfluordecanoic acid (PFDA) has been shown to exert an antiandrogenic effect in vivo by acting directly on the interstitial Leydig cells of the testis. The objective of this study was to examine the in vitro effects of PFDA and identify its site of action in steroidogenesis using as model systems the mouse tumor MA-10 and isolated rat Leydig cells. PFDA inhibited in a time- and dose-dependent manner the hCG-stimulated Leydig cell steroidogenesis. This effect was localized at the level of cholesterol transport into the mitochondria. PFDA did not affect either the total cell protein synthesis or the mitochondrial integrity. Moreover, it did not induce any DNA damage. Morphological studies indicated that PFDA induced lipid accumulation in the cells, probably due to the fact that cholesterol mobilized by hCG did not enter the mitochondria to be used for steroidogenesis. In search of the target of PFDA, we examined its effect on key regulatory mechanisms of steroidogenesis. PFDA did not affect the hCG-induced steroidogenic acute regulatory protein (StAR) levels. However, it was found to inhibit the mitochondrial peripheral-type benzodiazepine receptor (PBR) ligand binding capacity, 18-kDa protein, and messenger RNA (mRNA) levels. Further studies indicated that PFDA did not affect PBR transcription, but it rather accelerated PBR mRNA decay. Taken together, these data suggest that PFDA inhibits the Leydig cell steroidogenesis by affecting PBR mRNA stability, thus inhibiting PBR expression, cholesterol transport into the mitochondria, and the subsequent steroid formation. Moreover, this action of PFDA on PBR mRNA stability indicates a new mechanism of action of peroxisome proliferators distinct from the classic transcription-mediated regulation of target genes. |
| The phagocyte NADPH oxidase depends on cholesterol-enriched membrane microdomains for assembly Vilhardt, F. and B. van Deurs (2004), Embo J 23(4): 739-48. Abstract: The superoxide-producing phagocyte NADPH oxidase consists of a membrane-bound flavocytochrome b558 complex, and cytosolic factors p47phox, p67phox and the small GTPase Rac, which translocate to the membrane to assemble the active complex following cell activation. We here show that insolubility of NADPH oxidase subunits in nonionic detergents TX-100, Brij-58, and Brij-98 is a consequence of inclusion into cholesterol-enriched membrane microdomains (lipid rafts). Thus, flavocytochrome b558, in a cholesterol-dependent manner, segregated to the bouyant low-density detergent-resistant membrane (DRM) fraction, and the cytosolic NADPH oxidase factors associated dynamically with low-density DRM. Further, superoxide production following cholesterol depletion was severely compromised in intact cells or in a cell-free reconstituted system, correlating with a reduced translocation of cytosolic phox subunits to the membrane. In analogy with the widely accepted role of lipid rafts as signaling platforms, our data indicate that cholesterol-enriched microdomains act to recruit and/or organize the cytosolic NADPH oxidase factors in the assembly of the active NADPH oxidase. |
| The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol Piepho, R. W. (2000), Am J Cardiol 86(12A): 35L-40L. Abstract: Bile acid sequestrants, fibric acid derivatives (fibrates), hydroxy-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ("statins"), and niacin are able to increase HDL-C serum concentrations to varying degrees. Bile acid sequestrants are the least effective, whereas niacin is the most powerful agent for increasing HDL-C levels. Because of 2 alternate metabolic pathways of niacin breakdown, flushing or hepatotoxicity can occur in patients taking niacin. These effects can be mediated in a carefully designed formulation of niacin that releases the drug at a predictable rate. Niacin has few drug interactions and is a relatively inexpensive means of increasing HDL-C. A combination formulation that combines niacin plus a statin has shown promise in ongoing clinical trials. |
| The physician and pharmacist team. An effective approach to cholesterol reduction Bogden, P. E., L. M. Koontz, et al. (1997), J Gen Intern Med 12(3): 158-64. Abstract: OBJECTIVE: To assess the effect of a program that encourages teamwork between physicians and pharmacists on attempts to lower total cholesterol levels and to meet recommended goals proposed by the National Cholesterol Education Program (NCEP). DESIGN: A single-blind, randomized, controlled trial lasting 6 months. SETTING: An ambulatory primary care center. PATIENTS: A sample of 94 patients with total cholesterol levels of 240 mg/dL (6.2 mmol/L) or higher. INTERVENTION: Equal numbers of patients were randomly assigned to a control arm in which standard medical care was received and an intervention arm which implemented close interaction between physicians and pharmacists. MEASUREMENTS AND MAIN RESULTS: Absolute change in total cholesterol levels from baseline values and the percentage of patients who achieved an NCEP goal after 6 months of intervention were determined. The rate of success in achieving NCEP goals in the intervention arm was double the rate in the control arm (43% vs 21%, P <.05). Total cholesterol levels in the intervention arm declined 44 +/- 47 mg/dL (1.1 +/- 1.2 mmol/L) versus 13 +/- 51 mg/dL (0.3 +/- 1.3 mmol/L) in the control arm (p <.01). The effect of intervention on reducing total cholesterol levels was similar for men and women and did not appeared to be altered by age. The effect of intervention was greatest in patients with coronary heart disease (p <.01) followed by those without disease but with two or more coronary heart disease risk factors (p <.05). An effect of intervention was absent in patients without coronary heart disease and with fewer than two risk factors. CONCLUSIONS: Attempts to lower total cholesterol levels and achieve NCEP goals are likely to be more successful when combined with programs that include teamwork between physicians and pharmacists. Some programs, however, may be more successful for high-risk patients, for whom it is often easier to provide more aggressive therapies. Although altering adverse lipid profiles in lower-risk patients may be difficult, achieving optimal cholesterol levels could have an important impact on preventing movement to higher risk strata. |
| The possibility of prediction of cholesterol saturation of gallbladder bile Han, T. Q. (1990), Zhonghua Wai Ke Za Zhi 28(5): 285-8, 318. Abstract: Using stepwise regression we studied the possibility to determine the cholesterol saturation index (CSI) of gallbladder bile from analysis of fasting serum bile acid, 24 hour urine bile acid or serum lipids (cholesterol and triglyceride) in 31 gallstone patients. Two multiple regression equations were obtained to predict the CSI of bile from fasting serum bile acid compositions based on absolute concentration and relative concentration. The CSI of the gallbladder bile could not be predicted from 24 hour bile acid or serum lipids. Four critical values were calculated from regression equations, which predicted the CSI of bile with the efficiency above 70 percent. This study indicated for the first time that the prediction of CSI of gallbladder bile can be obtained from an analysis of fasting serum bile acid and hence it is possible to prevent gallstone formation at the stage of cholesterol supersaturated bile production. |
| The possibility of using carbon enterosorbents for normalizing cholesterol metabolism Davydov, V. I., S. S. Stavitskaia, et al. (1994), Biokhimiia 59(2): 304-12. Abstract: The kinetics of bile acids (BA) and cholesterol adsorption from biological fluids (bile) and reference solutions on carbon SCN were compared with conventional medical carbon with the view of elucidating the role of adsorption in improving cholesterol metabolism. It was found that the adsorptive capacity of carbon adsorbents is determined, primarily, by their porous structure as well by the chemical properties of the adsorbing surface. The enterosorbents were tested both in experimental animals and in clinical trials and are now successfully employed for preventing and treating atherosclerosis as well as for normalizing lipid metabolism. A procedure for surgical treatment combined with adsorptive detoxication (enterosorption) for patients with obstructive jaundice has been developed. |
| The possible association of decreased total cholesterol and severity of disease in elderly hospitalized patients Petersen, J. R., M. K. Linde, et al. (2000), Clin Chim Acta 290(2): 213-20. Abstract: The object of our study was to determine if any association exists between low serum cholesterol (< 4.14 mmol/l) and adverse outcomes in elderly patients > 60 years. Patients with low serum cholesterol were compared to a patient population with high serum cholesterol (> 6.22 mmol/l) and normal cholesterol (> or = 4.14 to < or = 6.22 mmol/l). Only hospitalized patients > 60 years, who were not on cholesterol lowering drugs, and did not have cardiovascular or liver disease were included in this study. The study group was 157 patients (79 with low, 78 with high, and 23 with normal cholesterol concentrations). Using the Kruskal-Wallis tests, the low cholesterol group was found to have statistically (p < 0.05) longer length of stay (average difference of > 11.1 days), higher hospital re-admission rate over a 1-year period (average difference of > 0.4 re-admissions), greater use of acute care services (average difference of > 0.6 days), and more emergency room (ER) visits over 1 year (average difference of > 0.5 admissions). |
| The possible role of genetic factors in the cholesterol high density lipoprotein level in the Moscow population Slominskii, P. A., V. A. Metel'skaia, et al. (2000), Genetika 36(10): 1401-5. Abstract: The study was aimed at clarifying the relative roles of genetic and environmental factors in determination of the blood concentration of high density lipoprotein cholesterol (HDL-C) in the Russian population. For this purpose, some polymorphic systems of the apolipoproteins B, CII, and CIII; cholesterol ether transport protein (CETP); and lecithin-cholesterol acyltransferase (LCAT) genes were compared in two groups of males living in Moscow who had high and low blood HDL-C concentrations (less than 40 and more than 50 mg/dl, respectively). No statistically significant differences were found between distributions of the allelic variants of the genes studied in males with different blood HDL-C concentrations. Thus, the given panel of proteins connected with the metabolism of blood plasma lipids has no effect on the blood HDL-C concentration in Russian males from the Moscow population. |
| The potential of fluorescent and spin-labeled steroid analogs to mimic natural cholesterol Scheidt, H. A., P. Muller, et al. (2003), J Biol Chem 278(46): 45563-9. Abstract: Cholesterol analogs are often used to investigate lipid trafficking and membrane organization of native cholesterol. Here, the potential of various spin (doxyl moiety) and fluorescent (7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) group) labeled cholesterol analogs as well as of fluorescent cholestatrienol and the naturally occurring dehydroergosterol to mimic the unique properties of native cholesterol in lipid membranes was studied in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes by electron paramagnetic resonance, nuclear magnetic resonance, and fluorescence spectroscopy. As cholesterol, all analogs undergo fluctuating motions of large amplitude parallel to the bilayer normal. Native cholesterol keeps a strict orientation in the membrane with the long axis parallel to the bilayer normal. Depending on the chemical modification or the position of the label, cholesterol analogs may adopt an "up-side-down" orientation in the membrane or may even fluctuate between "upright" and up-side-down orientation by rotational motions about the short axis not typical for native cholesterol. Those analogs are not able to induce a comparable condensation of phospholipid membranes as known for native cholesterol revealed by 2H nuclear magnetic resonance. However, cholesterol-induced lipid condensation is one of the key properties of native cholesterol, and, therefore, a well suited parameter to assess the potential of steroid analogs to mimic cholesterol. The study points to extreme caution when studying cholesterol behavior by the respective analogs. Among seven analogs investigated, only a spin-labeled cholesterol with the doxyl group at the end of the acyl chain and the fluorophore cholestatrienol mimic cholesterol satisfactorily. Dehydroergosterol has a similar upright orientation as cholesterol and could be used at low concentration (about 1 mol %), at which its lower potential to enhance lipid packing density does not perturb membrane organization. |
| The potential site of disordered gallbladder contractility during the early stage of cholesterol gallstone formation Mansour, A., I. Dawoud, et al. (1998), Hepatogastroenterology 45(23): 1404-9. Abstract: BACKGROUND/AIMS: Feeding a high cholesterol diet to dogs causes a reduction in gallbladder smooth muscle contractility with a consequent stasis. Gallbladder stasis is an important link between the hepatic secretion of cholesterol saturated bile and the formation of cholesterol gallstones. METHODOLOGY: In this study we tried to localize the probable site of gallbladder smooth muscle dysfunction in a well established animal model of cholesterol gallstone disease. Adult male dogs were fed either a high or low cholesterol diet (control group). Strips of gallbladder smooth muscle for tension development were stimulated with two groups of agonists and dose response curves were plotted for all agonists used. RESULTS: The forces developed in response to the first group of agonists, the cell membrane-active agonists, e.g. acetylcholine, cholecystokinin, and potassium chloride were decreased in high cholesterol fed dogs with an increased cholesterol saturation of bile when compared to the control group. On the other hand, the contractile response showed non-significant differences between the test and the control group on using the second group of agonists that bypass the intact sarcolemmal membrane and stimulate directly either the contractile mechanism, e.g. barium, or the intracellular signal transduction pathways e.g. aluminum fluoride. CONCLUSION: We conclude that the smooth muscle defect responsible for disordered gallbladder contractility in high cholesterol fed dogs most probably involves the sarcolemmal membrane. |
| The potential site of impaired gallbladder contractility in an animal model of cholesterol gallstone disease Xu, Q. W. and E. A. Shaffer (1996), Gastroenterology 110(1): 251-7. Abstract: BACKGROUND & AIMS: Gallbladder contractility is decreased in cholesterol gallstone disease, but the mechanism underlining this defect is unclear. The aim of this study was to determine the cellular site of this defect in an animal model of cholesterol gallstone disease. METHODS: Ground squirrels were maintained for 28 days on either a control or a 1% cholesterol diet. Gallbladder contractile responses to several known agonists were measured in vitro using smooth muscle strips. RESULTS: Gallbladder contractility in response to cholecystokinin, bethanechol, and K+ was equally decreased in cholesterol-fed animals, in concert with an increased cholesterol saturation of gallbladder bile compared with controls. In contrast, the contractile responses to A-23187 (a calcium ionophore), cyclopiazonic acid (a selective, potent inhibitor of sarcoplasmic reticulum Ca2+ pump), and barium (a calcium analogue), which readily diffuse across the intact sarcolemmal membrane, remained the same in both groups. Dose responses to a G-protein activator, aluminum fluoride, were again not different between these two groups. CONCLUSIONS: The primary smooth muscle defect in this animal model of cholesterol gallstone disease does not reside in the intracellular signal transduction pathways or in the contractile apparatus but instead involves the sarcolemmal membrane. |
| The pravastatin-induced decrease of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis in humans Kallien, G., K. Lange, et al. (1999), Hepatology 30(1): 14-20. Abstract: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress biliary cholesterol secretion and saturation. It remains unproven whether this is mediated by inhibition of cholesterol synthesis. Therefore, the effect of a long-term administration of pravastatin on cholesterogenesis and on biliary lipid secretion was investigated in seven healthy volunteers. Placebo or 40 mg of pravastatin were taken daily at bedtime for 5 weeks using a double-blind crossover design. During the last week, 12 hours after the last drug intake 0.04 mmol 1-13Cacetate/kg. h and 0.5 g polyethylene glycol 4,000/h were infused intraduodenally for 15 hours. Plasma and duodenal bile samples were collected hourly. Thereafter, the decay of 13Clabeled plasma cholesterol was measured during the following 3 days. The fractional and absolute syntheses of plasma and biliary cholesterol were determined by gas chromatography mass spectrometry using mass isotopomer distribution analysis. At the end of the pravastatin period plasma total and low-density lipoprotein (LDL) cholesterol had decreased by 20% and 24%, respectively. Similarly, pravastatin suppressed biliary secretion rates of cholesterol, total bile acids and phospholipids (P <.05) by 46%, 36%, and 51%. As a consequence, cholesterol saturation index remained unchanged. However, fractional syntheses of cholesterol were comparable (P >.05) on placebo compared with pravastatin with 3.1% versus 4.0% in plasma and 4.3% versus 5.2% in bile after 15 hours, respectively. The mean absolute synthesis rates amounted to 0.3 mg/kg/h on placebo versus 0.4 on pravastatin (P >. 05). In conclusion, the pravastatin-induced reduction of biliary cholesterol secretion is not directly related to an inhibition of cholesterol synthesis. |
| The prediction of the therapeutic response to cholesterol lowering drugs in an 11-year-old boy with homozygous familial hypercholesterolaemia Bakker, H. D., T. Bruin, et al. (1991), J Inherit Metab Dis 14(3): 389-92. |
| The predictive power of low-density lipoprotein cholesterol for coronary calcification Allison, M. A., M. Wright, et al. (2003), Int J Cardiol 90(2-3): 281-9. Abstract: BACKGROUND: Chronic elevation of low-density lipoprotein cholesterol is a major risk factor for developing atherosclerosis. The purpose of this study was to examine the correlation and predictive power of low-density lipoprotein cholesterol for calcified atheromatous disease as measured by electron beam computed tomography. METHODS: Six-thousand and ninety-three subjects underwent electron beam computed tomography of their coronary arteries, serum lipid testing, body fat determination and assessment of health status by questionnaire. Predictive power of low-density lipoprotein cholesterol for calcified atherosclerotic plaque was determined by correlations and multivariate logistic regression. RESULTS: The correlation between low-density lipoprotein cholesterol and calcified plaque score was very modest (r=0.055, P<0.001). There was a trend toward increasing calcified plaque with increasing levels of low-density lipoprotein cholesterol. Multivariate logistic regression revealed that low-density lipoprotein cholesterol is a modest but significant predictor of calcified coronary plaque. After adjusting for age, gender and high-density lipoprotein cholesterol, the risk of having any calcified plaque was 1.05-times higher for each 10 mg/dl increase in low-density lipoprotein cholesterol (P<0.001). Individuals with a low-density lipoprotein cholesterol level above 160 mg/dl had a 62% increase in odds for the presence of calcified plaque. CONCLUSIONS: Low-density lipoprotein cholesterol is weakly correlated with and predictive of calcified atherosclerotic plaque burden as measured by electron beam computed tomography. Higher levels of low-density lipoprotein cholesterol are associated with increased risk for the presence of calcified atheromas. |
| The presence and the role of chromatin cholesterol in rat liver regeneration Albi, E. and M. V. Magni (2002), J Hepatol 36(3): 395-400. Abstract: BACKGROUND/AIMS: It has been shown that cholesterol is necessary in early G1 phase during cell duplication. In the present research we have studied the presence of cholesterol in the hepatocyte chromatin lipid fraction and its behaviour in liver regeneration. METHODS: Hepatocyte nuclei and chromatin were isolated from normal and regenerating rat liver. The lipid fraction was extracted and analysed by chromatography. The activity of sphingomyelin-synthase in the chromatin was evaluated using labelled phosphatidylcholine. RESULTS: In the chromatin, the amount of cholesterol is similar to that of sphingomyelin, and it increases in chromatin digested with exogenous sphingomyelinase or proteinase K. It may be concluded that a complex, formed by cholesterol, sphingomyelin and proteins, is present in the chromatin. The particular affinity between sphingomyelin and cholesterol in chromatin with respect the nuclear membrane may be tentatively explained as due to the enrichment in saturated fatty-acids of the chromatin sphingomyelin. Moreover the cholesterol inhibits the chromatin sphingomyelin-synthase activity. During liver regeneration, an increase in chromatin cholesterol is observed between 6 and 18 h after hepatectomy, when the neutral-sphingomyelinase activity increases and the sphingomyelin-synthase is inhibited. CONCLUSIONS: The cholesterol is present in the chromatin and its amount changes in relation to cell proliferation in regenerating liver. |
| The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: a need for case-finding? Bindels, A. J., R. G. Westendorp, et al. (1999), Clin Endocrinol (Oxf) 50(2): 217-20. Abstract: OBJECTIVE: In order to determine whether screening of thyroid function is justified in patients with hypercholesterolaemia, we determined the prevalence of subclinical hypothyroidism at different levels of total plasma cholesterol in middle-aged men and women. DESIGN AND METHODS: 1200 participants were selected from a population based cross sectional study on risk factors for cardiovascular diseases. The participants were divided into three groups: total plasma cholesterol < 5 mmol/l, total plasma cholesterol 5-8 mmol/l, total plasma cholesterol > 8 mmol/l. Each group was comparable in size and sex distribution. Subclinical hypothyroidism was defined as plasma TSH levels higher than 4 mU/l, in the presence of normal free thyroxine (FT4(4)) concentration. RESULTS: Plasma samples of a total of 1191 participants were analyzed. The overall prevalence of subclinical hypothyroidism was 1.9% in men and 7.6% in women of middle age. In women the prevalence of subclinical hypothyroidism increased from 4.0 percent in the lowest, to 10.3 percent in the highest cholesterol stratum (P = 0.02). In men, the mean prevalence was 1.8 percent and roughly similar in the various strata. After age correction, an increase of 1 mU/l TSH in women was associated with an increase of 0.09 mmol/l total plasma cholesterol (95% confidence interval (CI) 0.02-0.16 mmol/l). A similar trend was found in men (0.16 mmol/l, 95% CI -0.02-0.34 mmol/l). CONCLUSIONS: In the population, the prevalence of subclinical hypothyroidism is up to 10 percent in middle aged women with high levels of total plasma cholesterol and may justify case-finding. In these women approximately 0.5 mmol/l of total plasma cholesterol can be attributed to the subclinical thyroid dysfunction. In men a similar correlation between thyroid dysfunction and total plasma cholesterol is seen, but the prevalence of thyroid dysfunction is considerably lower. |
| The primary prevention of cholesterol biliary lithiasis: the present and future Encinas Sotillos, A. and M. Bruguera Cortada (1999), Gastroenterol Hepatol 22(1): 22-7. |
| The prime role of plasma membrane cholesterol in the pathogenesis of immune evasion and clinical manifestations of falciparum malaria Sein, K. K. and M. Aikawa (1998), Med Hypotheses 51(2): 105-10. Abstract: The pathogenesis of falciparum malaria, with its immune evasion, mechanism of immune suppression and immunological inertia, the cause of its preferential incidence in children and pregnant mothers, and the pathological basis of clinical manifestations, are discussed from biochemical, biophysical and immunological perspectives. Sequestration and recrudescence are highlighted as the evolved means by which malaria parasites survive. These discussions are based on a novel hypothesis that changes in the lipid matrix fluidity of plasma membrane, through alterations of cholesterol and phospholipid content and variation in body temperature, significantly affect the membrane functions of cells. The pathogenesis of aggressive behavior in cerebral malaria is postulated to be different from that of coma, and complicated pregnancy in malaria is also discussed as a multifactorial condition wherein hypocholesterolemia, resulting from increased membrane biogenesis of multiplying parasites, is the common underlying factor. |
| The problem with cholesterol Dunnigan, M. G. (1993), Bmj 306(6889): 1355-6. |
| The problematic of decision-sharing: deconstructing 'cholesterol' in a clinical encounter Gwyn, R., G. Elwyn, et al. (2003), Health Expect 6(3): 242-54. Abstract: Shared decision-making is increasingly advocated as a means of interacting with patients but there is also a widely accepted view that many factors will militate against this ideal. While some patients may not wish to take on the responsibility of decision-making, it is also evident that many find it difficult to assimilate probabilities about future events and overestimate the likelihood of some outcomes, especially when terms such as 'stroke', 'bleeding' and 'heart attack' are used in consultation and bring with them emotional connotations and reactions. Under such circumstances, should clinicians portray risks as best they can, in the hope that even a marginally improved understanding will be an improvement on unilateral professional decision-making? Or, conversely, should they 'guide' the decision process, acting in a way that is known as 'professional agency'? Developing some perspectives put forward in recent work by the authors and applying it to a distinct clinical context, this paper will provide (i) a discourse analytic exploration of a single extended example from clinical practice employing aspects of Bakhtin's theory of dialogism, and (ii) a discussion and summary of what we can learn from this analysis in the context of shared decision-making and risk communication. |