| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| The benefits of reducing cholesterol levels: the need to distinguish primary from secondary prevention. 2. Implications for heart disease prevention in Australia Silberberg, J. S. and D. A. Henry (1991), Med J Aust 155(10): 670-4. Abstract: OBJECTIVE: To estimate the number of coronary heart disease (CHD) events arising from the primary and secondary prevention populations of middle-aged Australian men, and the potential impact in each setting of lipid-lowering therapy on death from CHD. DESIGN: Analysis based on results of a meta-analysis of drug trials to lower cholesterol levels and data from the Hunter Region Heart Disease Prevention Programme. MAIN OUTCOME MEASURE: Death from CHD. RESULTS: Over a five-year period, 1520 fatal CHD events would be expected in a population of 100,000 men aged 35 to 69 years. Approximately 52% would arise from subjects already known to suffer from CHD. We predict that treating everyone in the secondary prevention group who has a blood cholesterol level of greater than 5.2 mmol/L (approximately 5000 subjects) would prevent 118 deaths, compared with 51 deaths prevented by treating those in the primary prevention group who have cholesterol levels of greater than 6.2 mmol/L (approximately 30,000 subjects). The outcome is maintained in several sensitivity analyses. CONCLUSIONS: The majority of persons in whom death from CHD might be prevented by treatment to lower cholesterol levels can be identified by targeting subjects for secondary prevention. Therapy in the secondary prevention setting is much more efficient than in primary prevention. |
| The benign long-term effect of cholesterol crystal synovial cysts Gur, H. and M. Ehrenfeld (1994), Clin Rheumatol 13(3): 537-42. Abstract: Synovial effusions containing cholesterol crystals are uncommon. Most of the few reported cases have been found in patients with seropositive rheumatoid arthritis. In vitro studies, as well as an animal model, have suggested that cholesterol crystals could have a role in inflammation of the joints. In this report we present a case of seronegative arthritis, complicated by large carpal synovial cysts which contained numerous cholesterol crystals. The long-term presence of the cysts, without evidence of joint destruction, suggests that cholesterol crystal formation is probably a rare epiphenomenon, rather than a harbinger of inflammation. |
| The bilayer melting transition in lung surfactant bilayers: the role of cholesterol Larsson, M., K. Larsson, et al. (2003), Eur Biophys J 31(8): 633-6. Abstract: Aqueous dispersions of a porcine lung surfactant (PLS) extract with and without cholesterol supplementation were analyzed by X-ray scattering. Lamellar liquid-crystalline and gel-type bilayer phases are formed, as in pure phosphatidylcholine (PC)-cholesterol systems. This PLS extract, developed for clinical applications, has a cholesterol content of less than 1% (w/w). Above the limit of swelling, the bilayer structure shows a melting (main) transition during heating at about 34 degrees C. When 13 mol% cholesterol was added to PLS, so that the cholesterol content of natural lung surfactant was reached, the X-ray scattering pattern showed pronounced changes. The main transition temperature was reduced to the range 20-25 degrees C, whereas according to earlier studies of disaturated PC-cholesterol bilayers in water the main transition remains almost constant when the amount of solubilized cholesterol is increased. Furthermore, the changes in scattering pattern at passing this transition in PLS-cholesterol samples were much smaller than at the same transition in PLS samples. These effects of cholesterol solubilization can be related to phase segregation within the bilayers, known from pure PC-cholesterol systems. One phase, solubilizing about 8 mol% cholesterol, exhibits a melting transition, whereas the other bilayer phase, with a liquid-crystalline disordered conformation, has a cholesterol content in the range 20-30 mol% and this phase shows no thermal transition. The relative amount of bilayer lipids that is transformed at the main transition in the PLS-cholesterol sample is therefore only half compared to that in PLS samples. The reduction in transition temperature in the segregated bilayer of lung surfactant lipids is probably an effect of enrichment of disaturated PC species in the phase, which is poor in cholesterol. This work indicates that cholesterol in lung surfactant regulates the crystallization behavior. |
| The binding activity of the macrophage lipoprotein(a)/apolipoprotein(a) receptor is induced by cholesterol via a post-translational mechanism and recognizes distinct kringle domains on apolipoprotein(a) Keesler, G. A., B. R. Gabel, et al. (1996), J Biol Chem 271(50): 32096-104. Abstract: Elevated plasma levels of lipoprotein(a) (Lp(a)) can be a risk factor for atherosclerosis, and the interaction of Lp(a) with cholesterol-loaded macrophages (foam cells) in atheromata may be important in Lp(a)-induced atherogenesis. We have previously shown that when cultured macrophages are loaded with cholesterol, they acquire the ability to internalize and lysosomally degrade Lp(a) via interaction between a novel cell-surface receptor activity and the apolipoprotein(a) (apo(a)) moiety of Lp(a). Herein we explore the cell-surface binding of recombinant apo(a) (r-apo(a)) by foam cells. Whereas the induction of degradation of r-apo(a) by cholesterol loading of macrophages depended on new protein synthesis, the induction of binding of r-apo(a) did not. Furthermore, J774 macrophages bound r-apo(a) in a cholesterol-regulatable and specific manner but degraded r-apo(a) poorly. Thus, the binding and internalization/degradation functions of the receptor activity are distinct. To explore which domains on r-apo(a) interact with the foam cell receptor, we conducted a series of competitive and direct binding and degradation experiments using 12 r-apo(a) constructs that differed in their content of specific kringle subtypes. These data, as well as complementary data with anti-apo(a) monoclonal antibodies, indicated that the region centered around kringle type IV, subtypes 6-7 (KIV6-7) is important in receptor binding. Remarkably, a cholesterol-induced receptor activity with similar structural specificity was also found on Chinese hamster ovary cells. In conclusion, the foam cell Lp(a)/apo(a) receptor consists of a cholesterol-regulatable binding activity and a short-lived component necessary for internalization or lysosomal degradation; the binding activity interacts with a distinct region of apo(a) that is different from that involved in competition for plasminogen binding. |
| The binding of cholesterol and bile salts to recombinant rat liver fatty acid-binding protein Thumser, A. E. and D. C. Wilton (1996), Biochem J 320 (Pt 3): 729-33. Abstract: The physiological role of liver fatty acid-binding protein (L-FABP) has yet to be clarified. An important feature of this member of the family of intracellular lipid-binding proteins is the wide range of compounds that have been identified as potential physiological ligands. By using recombinant L-FABP, the binding of cholesterol, bile salts and their derivatives has been investigated under conditions that allow a direct comparison of the binding affinities of these ligands for fatty acids. The results demonstrate an inability of L-FABP to bind cholesterol, although the anionic derivative, cholesteryl sulphate, will bind under similar assay conditions. Of the bile salts examined, lithocholate and taurolithocholate sulphate showed the greatest binding to L-FABP. It is proposed that an important function of L-FABP is to bind certain physiological amphipathic anions, thus preventing the "free' concentrations of these compounds from exceeding their critical micelle concentration, which could result in cell damage. |
| The biomimetic Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)(+)decreases plasma insulin, cholesterol, and triglycerides in healthy and type II diabetic rats but not type I diabetic rats Sun, Y., B. J. Clodfelder, et al. (2002), J Biol Inorg Chem 7(7-8): 852-62. Abstract: The in vivo effects of administration of the synthetic, functional biomimetic cation Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)(+) to healthy and type I and type II diabetic model rats are described. In contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, the trinuclear cation has been shown in in vitro assays to interact with the insulin receptor, activating its kinase activity, presumably by trapping the receptor in its active conformation. Thus, treatment of rats with the trinuclear cation would be expected to result in changes in lipid and carbohydrate metabolism related to insulin action. After 24 weeks of intravenous administration (0-20 micro g Cr/kg body mass), the cation results in a concentration-dependent lowering of levels of fasting blood plasma LDL cholesterol, total cholesterol, triglycerides, and insulin and of 2-h plasma insulin and glucose levels after a glucose challenge; these results confirm a previous 12-week study examining the effect of the synthetic cation on healthy rats and are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. The cation has little, if any, effect on rats with STZ-induced diabetes (a type I diabetes model). However, Zucker obese rats (a model of the early stages of type II diabetes) after 24 weeks of supplementation (20 micro g/kg) have lower fasting plasma total, HDL, and LDL cholesterol, triglycerides, and insulin levels and lower 2-h plasma insulin levels. The lowering of plasma insulin concentrations with little effect on glucose concentrations suggests that the supplement increases insulin sensitivity. |
| The biomimetic Cr3O(O2CCH2CH3)6(H2O)3+ decreases plasma cholesterol and triglycerides in rats: towards chromium-containing therapeutics Sun, Y., K. Mallya, et al. (1999), J Biol Inorg Chem 4(6): 838-45. Abstract: The in vivo effects of administration of the synthetic, functional biomimetic Cr3O(O2CCH2CH3)6(H2O)3+ 1 and a naturally occurring, biologically active form of chromium, low-molecular-weight chromium-binding substance (LMWCr), to rats are described. Given that the complexes are proposed to function by interacting with insulin receptor, trapping it in its active conformation, in contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, changes in lipid and carbohydrate metabolism would be expected. After 12 weeks administration (20 micrograms/kg body mass), compound 1 results in 40% lower levels of blood plasma LDL cholesterol, 33% lower levels of total cholesterol, and significantly lower HDL cholesterol and triglyceride; these results are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. LMWCr, in contrast to 1, has no effect as it probably is degraded in vivo or excreted. These results are interpreted in terms of the mechanism of chromium action in response to insulin and the activation of insulin receptor, and the potential for the rational design of chromium-containing therapeutics is discussed. |
| The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1 Miyazaki, M., Y. C. Kim, et al. (2000), J Biol Chem 275(39): 30132-8. Abstract: Stearoyl-CoA desaturase (SCD) is a microsomal enzyme required for the biosynthesis of oleate and palmitoleate, which are the major monounsaturated fatty acids of membrane phospholipids, triglycerides, and cholesterol esters. Two well characterized isoforms of SCD, SCD1 and SCD2, exist in the mouse. Most mouse tissues express SCD1 and 2 with the exception of the liver, which expresses mainly the SCD1 isoform. We found that asebia mice homozygous for a natural mutation of the gene for SCD1 (SCD-/-) are deficient in hepatic cholesterol esters and triglycerides despite the presence of normal activities of acyl-CoA:cholesterol acyltransferase and glycerol phosphate acyltransferase, the enzymes responsible for cholesterol ester and triglyceride synthesis, respectively, in the liver of these mice. Feeding diets supplemented with triolein or tripalmitolein to the SCD-/- mice resulted in an increase in the levels of 16:1 and 18:1 in the liver but failed to restore the 18:1 and 16:1 levels of the cholesterol ester and triglycerides to the levels found in normal mice. The SCD-/- mouse had very low levels of triglycerides in the VLDL and LDL lipoprotein fractions compared with the normal animal. Transient transfection of an SCD1 expression vector into Chinese hamster ovary cells resulted in increased SCD activity and esterification of cholesterol to cholesterol esters. Taken together, our observations demonstrate that the oleoyl-CoA and palmitoleyl-CoA produced by SCD1 are necessary to synthesize enough cholesterol esters and triglycerides in the liver and suggest that regulation of SCD1 activity plays an important role in mechanisms of cellular cholesterol homeostasis. |
| The bisphosphonate ibandronate stimulates reverse cholesterol transport out of monocytoid cells by enhanced ABCA1 transcription Strobach, D. and R. L. Lorenz (2003), Biochem Biophys Res Commun 307(1): 23-30. Abstract: Nitrogen-containing bisphosphonates used in osteoporosis act by interference with pyrophosphorylated intermediates of the sterol pathway and are internalized by monocytes/macrophages, key players in atherogenesis. We therefore studied the effects of ibandronate on monocytic cholesterol homeostasis. In differentiated human MM6 cells and freshly prepared human PBMCs lipoprotein receptor transcription was quantified by real-time RT-PCR and receptor-mediated cellular cholesterol handling by lipoprotein-driven uptake and efflux assays. Low nanomolar concentrations of ibandronate reduced cellular cholesterol content despite reactive up-regulation of the LDL receptor. Simultaneously, the transcription of the cellular cholesterol exporter ABCA1 was severalfold stimulated, whereas the scavenger receptor CD36 was down-regulated. Thereby, ibandronate decreased the cellular uptake of modified LDL and enhanced the efflux of cholesterol to delipidated HDL. Geranylgeraniol antagonized the stimulation of ABCA1 expression by ibandronate. Ibandronate in low pharmacologic concentrations redirects monocytic cholesterol handling from favouring foam cell formation towards enhanced reverse cholesterol transport. |
| The bridging function of hepatic lipase clears plasma cholesterol in LDL receptor-deficient "apoB-48-only" and "apoB-100-only" mice Dichek, H. L., K. Qian, et al. (2004), J Lipid Res 45(3): 551-60. Abstract: Hepatic lipase clears plasma cholesterol by lipolytic and nonlipolytic processing of lipoproteins. We hypothesized that the nonlipolytic processing (known as the bridging function) clears cholesterol by removing apoB-48- and apoB-100-containing lipoproteins by whole particle uptake. To test our hypotheses, we expressed catalytically inactive human HL (ciHL) in LDL receptor deficient "apoB-48-only" and "apoB-100-only" mice. Expression of ciHL in "apoB-48-only" mice reduced cholesterol by reducing LDL-C (by 54%, 46 +/- 6 vs. 19 +/- 8 mg/dl, P < 0.001). ApoB-48 was similarly reduced (by 60%). The similar reductions in LDL-C and apoB-48 indicate cholesterol removal by whole particle uptake. Expression of ciHL in "apoB-100-only" mice reduced cholesterol by reducing IDL-C (by 37%, 61 +/- 19 vs. 38 +/- 12 mg/dl, P < 0.003). Apo-B100 was also reduced (by 27%). The contribution of nutritional influences was examined with a high-fat diet challenge in the "apoB-100-only" background. On the high fat diet, ciHL reduced IDL-C (by 30%, 355 +/- 72 vs. 257 +/- 64 mg/dl, P < 0.04) but did not reduce apoB-100. The reduction in IDL-C in excess of apoB-100 suggests removal either by selective cholesteryl ester uptake, or by selective removal of larger, cholesteryl ester-enriched particles. Our results demonstrate that the bridging function removes apoB-48- and apoB-100-containing lipoproteins by whole particle uptake and other mechanisms. |
| The C- and the N-terminal regions of glycoprotein 41 ectodomain fuse membranes enriched and not enriched with cholesterol, respectively Shnaper, S., K. Sackett, et al. (2004), J Biol Chem 279(18): 18526-34. Abstract: To infect target cells, HIV-1 employs a virally encoded transmembrane protein (gp41) to fuse its viral envelope with the target cell plasma membrane. We describe the gp41 ectodomain as comprised of N- and C-terminal subdomains, each containing a heptad repeat as well as a fusogenic region, whose organization is mirrored by the intervening loop region. Recent evidence indicates that the gp41 directed fusion reaction proceeds to initial pore formation prior to gp41 folding into its low energy hairpin conformation. This implies that exposed regions of the gp41 ectodomain are responsible for the bulk of the fusion work, probably through direct protein-membrane interactions. Prevalent fusion models contend that the gp41 ectodomain initially interacts with the target cell surface through its highly hydrophobic N terminus, which is believed to insert into the target membrane, thereby linking the virus to the target cell. This arrangement allows the N-terminal subdomain to interact with the target cell surface, whereas the C-terminal subdomain remains proximal to the virion, allowing interaction with the viral envelope. The composition of the viral envelope and the target cell surface differ due to the virus budding from raft microdomains. We show here that constructs corresponding to the C-terminal subdomain specifically destabilize ordered and cholesterol rich membranes (33 molar %), whereas the N-terminal subdomain is more effective in fusing both unordered cholesterol-free membranes and those containing lower amounts of cholesterol (10 molar %). Moreover we show that, in the context of the C-terminal subdomain, the heptad repeat contributes helical structure, which may describe the enhanced inhibitory effect of the C-terminal subdomain relative to the C-terminal heptad repeat (C34) alone. Our results are discussed in light of recent findings that showcase the role of exposed gp41 regions in effecting membrane fusion. |
| The C282Y/wt heterozygous HFE genotype is associated with lower blood pressure and HDL-cholesterol in Type 2 diabetes Hermans, M. P., S. Van Lerberghe, et al. (2002), Diabet Med 19(9): 796. |
| The CAG repeat polymorphism in the androgen receptor gene is associated with HDL-cholesterol but not with coronary atherosclerosis or myocardial infarction Hersberger, M., J. Muntwyler, et al. (2005), Clin Chem 51(7): 1110-5. Abstract: BACKGROUND: Age-adjusted morbidity and mortality rates from coronary heart disease (CHD) are higher in men than in women. Androgens are suspected to be responsible for the male disadvantage. The genomic effect of androgens is mediated by the androgen receptor (AR), which has a polymorphic CAG repeat in exon 1. The number of repeats is inversely related to the transcriptional activity of the AR on target genes. METHODS: We investigated the association of this CAG repeat polymorphism with CHD and myocardial infarction (MI) in 2 independent case-control studies involving 544 Caucasian men. RESULTS: The number of CAG repeats in the AR gene correlated significantly with HDL-cholesterol (HDL-C) in controls (r = 0.21; P = 0.015). This effect was independent of triglycerides, body mass index, alcohol intake, smoking, and age in a multiple regression model (R(2) = 50%). Despite decreased HDL-C, lower CAG repeat numbers were not associated with increased risk for CHD (odds ratio = 0.82; 95% confidence interval, 0.50-1.36; P = 0.44) or MI in carriers of AR genes with lower CAG repeat numbers (odds ratio = 0.72; 95% confidence interval, 0.37-1.39; P = 0.33). CONCLUSIONS: Shorter, more androgenic AR alleles with fewer CAG repeats are associated with lower HDL-C, but not with an increased risk for CHD or MI, which argues against a detrimental androgen effect on cardiovascular risk under physiologic conditions. |
| The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity Zitzmann, M., M. Brune, et al. (2001), J Clin Endocrinol Metab 86(10): 4867-73. Abstract: Genomic effects of T are exerted via the AR. The length of the polymorphic CAG repeat sequence in the AR gene is inversely correlated with the transcriptional regulation of target genes by T. In 110 healthy men (20-50 yr), we investigated the interactions among this polymorphism, serum levels of sex hormones, cardiovascular risk factors, and flow-mediated and nitrate-induced vasodilatation of the brachial artery. The number of CAG repeat had no significant correlations with serum concentrations of total or free T. Stepwise multiple regression analysis revealed positive correlations of the number of CAG repeat with serum levels of high density lipoprotein cholesterol (partial r = 0.44; P < 0.001) and flow-mediated vasodilatation (partial r = 0.37; P < 0.001). The association of CAG repeat with high density lipoprotein (HDL) cholesterol was independent of body fat content and serum levels of free T, which both had significant negative correlations with HDL cholesterol. The association of CAG repeat with flow-mediated vasodilatation was independent of cigarette smoking and serum levels of free T and low density lipoprotein cholesterol, which also were correlated with flow-mediated vasodilatation. We conclude that a low number of CAG repeat in the AR gene implies a greater chance for low levels of HDL cholesterol and reduced endothelial response to ischemia, which are both important risk factors for coronary heart disease. |
| The calf thymus superoxide dismutase: a protein active on cholesterol metabolism Mondola, P. (1993), Comp Biochem Physiol B 105(3-4): 457-64. Abstract: 1. Recent studies on the new aspects of thymus physiology describing the correlation between thymus hormones and pituitary hormone secretion, are illustrated. 2. Subsequently, results of a series of experiments showing the effect of a calf thymus protein on cholesterol synthesis in rat hepatocyte cells are discussed. 3. The last part of this review is focused on the biochemical characteristics of this calf thymus protein that revealed an amino acid sequence that was found to be identical with regions of bovine erythrocyte superoxide dismutase. New perspectives of studies, focused on the isolation of possible superoxide dismutase membrane receptors, are described at the end of this review. |
| The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans Walford, R. L., S. B. Harris, et al. (1992), Proc Natl Acad Sci U S A 89(23): 11533-7. Abstract: Biosphere 2 is a 3.15-acre space containing an ecosystem that is energetically open (sunlight, electric power, and heat) but materially closed, with air, water, and organic material being recycled. Since September 1991, eight subjects (four women and four men) have been sealed inside, living on food crops grown within. Their diet, low in calories (average, 1780 kcal/day; 1 kcal = 4.184 kJ), low in fat (10% of calories), and nutrient-dense, conforms to that which in numerous animal experiments has promoted health, retarded aging, and extended maximum life span. We report here medical data on the eight subjects, comparing preclosure data with data through 6 months of closure. Significant changes included: (i) weight, 74 to 62 kg (men) and 61 to 54 kg (women); (ii) mean systolic/diastolic blood pressure (eight subjects), 109/74 to 89/58 mmHg (1 mmHg = 133 Pa); (iii) total serum cholesterol, from 191 +/- 11 to 123 +/- 9 mg/dl (mean +/- SD; 36% mean reduction), and high density lipoprotein, from 62 +/- 8 to 38 +/- 5 (risk ratio unchanged); (iv) triglyceride, 139 to 96 mg/dl (men) and 78 to 114 mg/dl (women); (v) fasting glucose, 92 to 74 mg/dl; (vi) leukocyte count, 6.7 to 4.7 x 10(9) cells per liter. We conclude that drastic reductions in cholesterol and blood pressure may be instituted in normal individuals in Western countries by application of a carefully chosen diet and that a low-calorie nutrient-dense regime shows physiologic features in humans similar to those in other animal species. |
| The cardiology patient page. Statins: powerful drugs for lowering cholesterol: advice for patients Gotto, A. M., Jr. (2002), Circulation 105(13): 1514-6. |
| The case against childhood cholesterol screening Newman, T. B., W. S. Browner, et al. (1990), Jama 264(23): 3039-43. Abstract: Because some authorities have proposed blood cholesterol screening for children to prevent coronary heart disease, we reviewed published studies to estimate the potential risks and benefits of such screening. Childhood cholesterol levels are a poor predictor of high cholesterol levels in young adulthood and will be an even poorer predictor of coronary heart disease later in life. There is no evidence that blood cholesterol levels can be lowered more easily in children than in adults, and it seems unlikely that cholesterol reduction in childhood will be much more effective at preventing coronary heart disease than cholesterol reduction begun in middle age. Screening and interventions to lower blood cholesterol levels for millions of children would be expensive, could lead to labeling and family conflicts, and may cause malnutrition and increased noncardiovascular mortality. Because the benefits of cholesterol screening are unlikely to exceed these risks, we conclude that children should not be screened for high blood cholesterol levels. |
| The case against 'the case against childhood cholesterol screening' Resnicow, K., G. Berenson, et al. (1991), Jama 265(22): 3003-5. |
| The case of the common duct stone: cholesterol revisited DePalma, R. G. (1999), Arch Surg 134(12): 1398-9. |