| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Re: Kawai et al.--Bacteria are not important in the formation of pure cholesterol stones Cariati, A. and F. Cetta (2002), Am J Gastroenterol 97(11): 2921-2; author reply 2922-3. |
| Reaching National Cholesterol Education Program Goals: a managed care approach to improving hyperlipidemia disease management outcomes. Introduction Jacobson, T. A. (2001), Am J Med 110 Suppl 6A: 1S-2S. |
| Reaction of phosphatidylcholine hydroperoxide in human plasma: the role of peroxidase and lecithin:cholesterol acyltransferase Nagata, Y., Y. Yamamoto, et al. (1996), Arch Biochem Biophys 329(1): 24-30. Abstract: In order to elucidate the reason why phosphatidylcholine hydroperoxide is unstable in human plasma, 1-palmitoyl-2-linoleoylphosphatidylcholine hydroperoxide (PLPC-OOH) was incubated aerobically in human plasma at 37 degrees C, and its decomposition products were measured. The major product was the corresponding alcohol (PLPC-OH) and this reduction probably occurred by an enzymatic process since no acceleration in ascorbate depletion and no significant decrease in other plasma antioxidants were observed upon addition of PLPC-OOH. Cholesteryl linoleate hydroperoxide and its alcohol (Ch18:2-OH) were also detected as minor products. Similarly, 1-stearoyl-2-arachidonoylphosphatidylcholine hydroperoxide gave its alcohol (SAPC-OH) as a major product and cholesteryl arachidonate hydroperoxide and its hydroxide (Ch20:4=OH) as minor products. These oxidized cholesteryl esters are likely to be produced by the action of lecithin:cholesterol acyltransferase (LCAT) present in high-density lipoprotein (HDL) since (a) incubation of PLPC-OH and SAPC-OH in human plasma gave Ch18:2-OH and Ch20:4-OH, respectively, (b) isolated human HDL converted PLPC-OH to Ch18:2 OH and SAPC-OH to Ch20:4-OH while isolated human low-density lipoprotein was inactive for this conversion, and (c) formation of oxidized cholesteryl esters in plasma and HDL was inhibited by the LCAT inhibitor 5,5'-dithiobis(2-nitrobenzoic acid). A possible beneficial role of LCAT for converting phosphatdylcholine hydroperoxide to cholesteryl ester hydroperoxide is also discussed. |
| Reactions of direct LDL-cholesterol assays with pure LDL fraction and IDL: comparison of three homogeneous methods Sakaue, T., T. Hirano, et al. (2000), Clin Chim Acta 295(1-2): 97-106. Abstract: According to the definition of the Lipid Research Clinic's protocol, low-density lipoprotein (LDL) refers to the lipoprotein of density (d)=1.006-1.063 g/ml which contains another atherogenic lipoprotein, IDL (d=1.006-1.019 g/ml). Because metabolic properties are largely different between LDL and IDL, LDL is now defined as the lipoprotein of d=1.019-1.063 g/ml. Recently direct LDL-cholesterol assay kits using novel surfactants (the homogeneous methods) have become commercially available and widely used in Japan. The aim of this study is to examine how three direct LDL-cholesterol assay kits, LDL-EX, Choletest-LDL and Determinor-L LDL, react with pure LDL (d=1. 019-1.063 g/ml) and IDL (1.006-1.019 g/ml) fractions isolated by ultracentrifugation. Thirty-one healthy subjects and one type III dysbetalipoproteinemic patient were enrolled in this study. All homogeneous methods highly correlated with LDL-cholesterol (r=0.95-0. 98), although the values for LDL-EX were closer to the values for ultracentrifugation than were those of the other two methods (95 vs. 86-87%, P<0.0001). Cross-reactivity with IDL was 31, 47 and 64% for LDL-EX, Choletest-LDL, and Determinor-L LDL, respectively. Similar results were obtained in the IDL from a type III dysbetalipoproteinemic patient. These results suggest that LDL-cholesterol measured by LDL-EX better reflects pure LDL fraction with weaker cross-reaction with IDL than other homogeneous methods. |
| Reactive oxygen metabolites promote cholesterol crystal formation in model bile: role of lipid peroxidation Eder, M. I., J. F. Miquel, et al. (1996), Free Radic Biol Med 20(5): 743-9. Abstract: In animal models of gallstone disease inflammatory alterations of the gallbladder mucosa are regularly found before the first appearance of cholesterol monohydrate crystals in bile. At sites of inflammation granulocytes generate reactive oxygen metabolites (ROM). The aim of our study was to investigate whether ROM may influence the cholesterol monohydrate crystal formation in supersaturated model bile. Superoxide anions (O2-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH) were generated by the interaction of Fe(3+)-EDTA with ascorbic acid (Asc). The influence of ROM on cholesterol crystal formation was studied by measurement of the nucleation time. To check whether lipid peroxidation was induced by the ROM generation, production of malondialdehyde equivalents was measured in bile with the thiobarbituric assay. Furthermore, the lipid pattern of bile after ROM exposure was analyzed by thin layer chromatography. Addition of Fe(3+)-EDTA/Asc to model bile markedly decreased the cholesterol nucleation time (NT) (p < 0.01), caused a significant increase in malonidialdehyde equivalents (p < 0.001) and induced the generation of 4-hydroxy-2,3-trans-nonenal (4-HNE). In an attempt to identify a specific oxygen metabolite responsible for the alterations in bile, the effects of various oxygen radical scavengers were tested. Desferal, which prevents -OH generation by chelation of ferrous iron, completely protected bile against Fe(3+)-EDTA/Asc-induced decrease in NT (p < 0.001), increase in lipid peroxidation (p < 0.001) and generation of 4-HNE. Our results indicate that formation of cholesterol crystals in model bile is enhanced by ROM. Hydroxyl radical induced lipid peroxidation appears to be the mechanism responsible for the crystallisation promoting activity of ROM. |
| Reactive reasoning. Is an inflammation protein the next cholesterol? Martindale, D. (2005), Sci Am 292(4): 10-1. |
| Reagent-free, simultaneous determination of serum cholesterol in HDL and LDL by infrared spectroscopy Liu, K. Z., R. A. Shaw, et al. (2002), Clin Chem 48(3): 499-506. Abstract: BACKGROUND: The purpose of this study was to assess the feasibility of infrared (IR) spectroscopy for the simultaneous quantification of serum LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) concentrations. METHODS: Serum samples (n = 90) were obtained. Duplicate aliquots (5 microL) of the serum specimens were dried onto IR-transparent barium fluoride substrates, and transmission IR spectra were measured for the dry films. In parallel, the HDL-C and LDL-C concentrations were determined separately for each specimen by standard methods (the Friedewald formula for LDL-C and an automated homogeneous HDL-C assay). The proposed IR method was then developed with a partial least-squares (PLS) regression analysis to quantitatively correlate IR spectral features with the clinical analytical results for 60 randomly chosen specimens. The resulting quantification methods were then validated with the remaining 30 specimens. The PLS model for LDL-C used two spectral ranges (1700-1800 and 2800-3000 cm(-1)) and eight PLS factors, whereas the PLS model for HDL-C used three spectral ranges (800-1500, 1700-1800, and 2800-3500 cm(-1)) with six factors. RESULTS: For the 60 specimens used to train the IR-based method, the SE between IR-predicted values and the clinical laboratory assays was 0.22 mmol/L for LDL-C and 0.15 mmol/L for HDL-C (r = 0.98 for LDL-C; r = 0.91 for HDL-C). The corresponding SEs for the test spectra were 0.34 mmol/L (r = 0.96) and 0.26 mmol/L (r = 0.82) for LDL-C and HDL-C, respectively. The precision for the IR-based assays was estimated by the SD of duplicate measurements to be 0.11 mmol/L (LDL-C) and 0.09 mmol/L (HDL-C). CONCLUSIONS: IR spectroscopy has the potential to become the clinical method of choice for quick and simultaneous determinations of LDL-C and HDL-C. |
| Real-time analysis of the effects of cholesterol on lipid raft behavior using atomic force microscopy Lawrence, J. C., D. E. Saslowsky, et al. (2003), Biophys J 84(3): 1827-32. Abstract: Cholesterol plays a crucial role in cell membranes, and has been implicated in the assembly and maintenance of sphingolipid-rich rafts. We have examined the cholesterol-dependence of model rafts (sphingomyelin-rich domains) in supported lipid monolayers and bilayers using atomic force microscopy. Sphingomyelin-rich domains were observed in lipid monolayers in the absence and presence of cholesterol, except at high cholesterol concentrations, when separate domains were suppressed. The effect of manipulating cholesterol levels on the behavior of these sphingomyelin-rich domains in bilayers was observed in real time. Depletion of cholesterol resulted in dissolution of the model lipid rafts, whereas cholesterol addition resulted in an increased size of the sphingomyelin-rich domains and eventually the formation of a single raftlike lipid phase. Cholesterol colocalization with sphingomyelin-rich domains was confirmed using the sterol binding agent filipin. |
| Real-world effectiveness of lipid-lowering therapy in male and female outpatients with coronary heart disease: relation to pre-treatment low-density lipoprotein-cholesterol, pre-treatment coronary heart disease risk, and other factors Krobot, K. J., D. D. Yin, et al. (2005), Eur J Cardiovasc Prev Rehabil 12(1): 37-45. Abstract: BACKGROUND: Determinants of the real-world effectiveness of lipid-lowering therapy have been rarely assessed in an unselected observational coronary heart disease (CHD) community cohort over time. DESIGN: Randomly drawn patients (n=605) from randomly drawn practices (n=62) were retrospectively followed for a median of 3.6 years (1998-2002) on lipid-lowering therapy (98% statins). METHODS: Coronary heart disease population-averaged estimates and variances accounting for repeated measurements within patients were obtained using generalized estimating equations. RESULTS: Post-treatment low-density lipoprotein-cholesterol (LDL-C) was 124 mg/dl in men and 141 mg/dl in women and was independently associated (all P<0.05) with pre-treatment LDL-C (+3.7 mg/dl per 10 mg/dl increment), female sex (+14.0 mg/dl), coronary bypass (-9.5 mg/dl), drug-treated diabetes mellitus (-6.8 mg/dl), and era 2002/2001 versus 1999/2000 (-6.4 mg/dl) in age-adjusted multivariate analyses. Holding pre-treatment LDL-C constant post-treatment LDL-C was associated with pre-treatment Framingham CHD risk in men (-13.9 mg/dl per doubling of risk), whereas LDL-C control in women resembled that in low-risk men. The likelihood of attaining LDL-C <100 mg/dl was 0.28 in men and 0.17 in women and was likewise associated with the above factors. CONCLUSION: Low-density lipoprotein-cholesterol control remained low despite lipid-lowering therapy across a wide range of pre-treatment LDL-C and pre-treatment CHD risk. Low-density lipoprotein-cholesterol control in women was inferior to that in men, a finding that warrants attention and clarification. |
| Re-assessing the contribution of serum total cholesterol, blood pressure and cigarette smoking to the aetiology of coronary heart disease: impact of regression dilution bias Emberson, J. R., P. H. Whincup, et al. (2003), Eur Heart J 24(19): 1719-26. Abstract: AIMS: To estimate the combined contribution of serum total cholesterol, blood pressure and cigarette smoking to coronary heart disease (CHD) risk after adjustment for regression dilution bias. METHODS AND RESULTS: Six thousand, five hundred and thirteen middle-aged British men without CHD were followed for major CHD events over 10 years. The population attributable risk fraction (PARF) was predicted for a range of risk factor thresholds before and after adjustment for regression dilution of serum total cholesterol and blood pressure. Defining 'low-risk' individuals as being in the bottom tenth of the population distributions of serum total cholesterol (<5.2 mmol/l) and diastolic blood pressure (<70 mmHg) and a non-cigarette smoker, the PARF was 75%, increasing to 86% after adjustment for regression dilution. Regardless of the threshold criteria chosen, the PARF was substantially greater than 65% before adjustment for regression dilution and greater than 75% after adjustment. Exclusion of ex-smokers and passive smokers from the low-risk group increased estimates further. Adjustment for other coronary risk factors had little effect on the results. CONCLUSIONS: At least 80% of major CHD events in middle-aged men can be attributed to the three strongest risk factors. Population-wide control of these factors is crucial for effective CHD prevention. |
| Reassessment of National Cholesterol Education Program Adult Treatment Panel-III guidelines: one year later Ansell, B. J. and D. D. Waters (2002), Am J Cardiol 90(5): 524-5. |
| Recent advances in brain cholesterol dynamics: transport, domains, and Alzheimer's disease Wood, W. G., F. Schroeder, et al. (1999), Lipids 34(3): 225-34. Abstract: Major advances in understanding cholesterol dynamics and the role that cholesterol plays in vascular disease have recently been made. The brain is an organ that is highly enriched in cholesterol, but progress toward understanding brain cholesterol dynamics has been relatively limited. This review examines recent contributions to the understanding of brain cholesterol dynamics, focusing on extracellular and intracellular lipid carrier proteins, membrane cholesterol domains, and emerging evidence linking an association between cholesterol dynamics and Alzheimer's disease. |
| Recent advances in membrane cholesterol domain dynamics and intracellular cholesterol trafficking Schroeder, F., A. A. Frolov, et al. (1996), Proc Soc Exp Biol Med 213(2): 150-77. Abstract: Cholesterol is distributed nonrandomly in and between biological membranes. Despite over two decades' investigation of these phenomena, the origin, regulation, and function of membrane cholesterol asymmetry are not known. Likewise, although pathways of cellular cholesterol absorption/utilization as well as de novo synthesis have been investigated in depth, parallel progress in elucidating pathways of intracellular cholesterol trafficking and final deposition of cholesterol within membranes remains undefined. Understanding the nature and regulation of these processes is essential to resolving molecular mechanisms of cholesterol uptake, reverse cholesterol transport, steroidogenesis, and modulation of membrane function. Based on the fundamental observation that cholesterol is not distributed uniformly in the cell, three key concepts have contributed to recent advances in this field: First, cholesterol is asymmetrically distributed across the cell surface plasma membrane, wherein it translocates rapidly. Second, cholesterol is distributed within the plane of biomembrane bilayers into dynamic and static domains, with the latter predominating. The exact nature and physiological functions of such cholesterol domains or pools remain an enigma. Third, regulation of the size and kinetics of biomembrane cholesterol domains may be determining factors in intracellular cholesterol trafficking, targeting, and efflux. Contributions of both cytosolic carrier proteins and vesicular processes are recognized. |
| Recent advances in membrane microdomains: rafts, caveolae, and intracellular cholesterol trafficking Schroeder, F., A. M. Gallegos, et al. (2001), Exp Biol Med (Maywood) 226(10): 873-90. Abstract: Cellular cholesterol homeostasis is a balance of influx, catabolism and synthesis, and efflux. Unlike vascular lipoprotein cholesterol transport, intracellular cholesterol trafficking is only beginning to be resolved. Exogenous cholesterol and cholesterol ester enter cells via the low-density lipoprotein (LDL) receptor/lysosomal and less so by nonvesicular, high-density lipoprotein (HDL) receptor/caveolar pathways. However, the mechanism(s) whereby cholesterol enters the lysosomal membrane, translocates, and transfers out of the lysosome to the cell interior are unknown. Likewise, the steps whereby cholesterol enters the cytofacial leaflet of the plasma membrane caveolae, rapidly translocates, leaves the exofacial leaflet, and transfers to extracellular HDL are unclear. Increasing evidence obtained with model and isolated cell membranes, transfected cells, genetic mutants, and gene-ablated mice suggests that proteins such as caveolin, sterol carrier protein-2 (SCP-2), Niemann-Pick C1 protein, steroidogenic acute regulatory protein (StAR), and other intracellular proteins mediate intracellular cholesterol transfer. While these proteins bind cholesterol and/or interact with cholesterol-rich membrane microdomains (e.g., caveolae, rafts, and annuli), their relative contributions to direct molecular versus vesicular cholesterol transfer remain to be resolved. The formation, regulation, and role of membrane microdomains in regulating cholesterol uptake/efflux and trafficking are unclear. Some cholesterol-binding proteins exert opposing effects on cellular cholesterol uptake/efflux, transfer of cholesterol out of the lysosomal membrane, and/or intracellular cholesterol trafficking to select membranous organelles. Resolving these cholesterol pathways and the role of membrane cholesterol microdomains is essential to our understanding not only of processes that affect cholesterol metabolism, but also of the abnormal regulation that may lead to disease (diabetes, obesity, atherosclerosis, neutral lipid storage, Niemann-Pick C, congenital lipoid adrenal hyperplasia, etc.). |
| Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options Stone, N. J., S. Bilek, et al. (2005), Am J Cardiol 96(4A): 53E-59E. Abstract: In the summer of 2004, an evidence-based update of the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for management of hypercholesterolemia was published. This detailed assessment of 5 major clinical trials, published since the ATP III report in 2001, was designed to provide guidance for physicians in decision making for patients at high risk and very high risk. We have tried to summarize this assessment by suggesting the following to clinicians: (1) Calculate global risk of coronary artery disease (CAD) to determine an overall strategy for cholesterol management. (2) Emphasize the benefits of diet, exercise, and weight control or therapeutic lifestyle change, especially in those with lifestyle risk factors. (3) Use 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (statins) as first-line drugs to reduce risk of CAD and stroke in those at moderate to high risk. (4) If statins are prescribed, use moderate doses that reduce plasma levels of low-density lipoprotein (LDL) cholesterol by > or = 30% to 40%. (5) Strongly consider statin therapy in those with diabetes (with the exception of severe hypertriglyceridemia). (6) Consider LDL cholesterol-lowering drug therapy for lipids in older patients at risk. (7) Consider adding either a fibrate or nicotinic acid in high-risk patients with elevated plasma triglyceride values or low levels of plasma high-density lipoprotein cholesterol after statin therapy has achieved the LDL cholesterol goal. (8) Continue to treat those at low risk in similar fashion as before. This update is to inform current physician judgment in this area. Further clinical trial data that may modify or extend these recommendations are eagerly awaited. |
| Recent view of intracellular cholesterol transport Arai, H. (1994), Tanpakushitsu Kakusan Koso 39(9): 1518-31. |
| Receptor offers clues to how 'good' cholesterol works Husten, L. (1997), Science 278(5341): 1228. |
| Recessive x-linked ichthyosis: role of cholesterol-sulfate accumulation in the barrier abnormality Zettersten, E., M. Q. Man, et al. (1998), J Invest Dermatol 111(5): 784-90. Abstract: Cholesterol sulfate is a multifunctional sterol metabolite, produced in large amounts in squamous keratinizing epithelia. Because patients with recessive x-linked ichthyosis display not only a 10-fold increase in cholesterol sulfate, but also a 50% reduction in cholesterol, we assessed here whether cholesterol sulfate accumulation and/or cholesterol deficiency produce abnormal barrier function in recessive x-linked ichthyosis. Patients with recessive x-linked ichthyosis display both an abnormal barrier under basal conditions, and a delay in barrier recovery after acute perturbation, which correlate with minor abnormalities in membrane structure and extensive lamellar-phase separation. Moreover, both the functional and the structural abnormalities were corrected by topical cholesterol. Yet, topical cholesterol sulfate produced both a barrier abnormality in intact skin and extracellular abnormalities in isolated stratum corneum, effects largely reversed by coapplications of cholesterol. Together, these results suggest that cholesterol sulfate accumulation rather than cholesterol deficiency is responsible for the barrier abnormality. Despite the apparent importance of cholesterol sulfate-to-cholesterol processing for normal barrier homeostasis, neither steroid sulfatase activity nor mRNA levels are upregulated following acute perturbations. These results demonstrate both a potential role for cholesterol sulfate-to-cholesterol processing in normal permeability barrier homeostasis, and that basal levels of steroid sulfatase are sufficient to accommodate acute insults to the permeability barrier. |
| Recollections of pioneers in nutrition: from starvation to cholesterol Keys, A. (1990), J Am Coll Nutr 9(4): 288-91. |
| Recombinant acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) purified to essential homogeneity utilizes cholesterol in mixed micelles or in vesicles in a highly cooperative manner Chang, C. C., C. Y. Lee, et al. (1998), J Biol Chem 273(52): 35132-41. Abstract: Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an integral membrane protein located in the endoplasmic reticulum. It catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acyl coenzyme A. The first gene encoding the enzyme, designated as ACAT-1, was identified in 1993 through an expression cloning approach. We isolated a Chinese hamster ovary cell line that stably expresses the recombinant human ACAT-1 protein bearing an N-terminal hexahistidine tag. We purified this enzyme approximately 7000-fold from crude cell extracts by first solubilizing the cell membranes with the zwitterionic detergent 3-(3-cholamidopropyl)dimethylammonio-1-propanesulfonate, then proceeding with an ACAT-1 monoclonal antibody affinity column and an immobilized metal affinity column. The final preparation is enzymologically active and migrates as a single band at 54 kDa on SDS-polyacrylamide gel electrophoresis. Pure ACAT-1 dispersed in mixed micelles containing sodium taurocholate, phosphatidylcholine, and cholesterol remains catalytically active. The cholesterol substrate saturation curves of the enzyme assayed either in mixed micelles or in reconstituted vesicles are both highly sigmoidal. The oleoyl-coenzyme A substrate saturation curves of the enzyme assayed under the same conditions are both hyperbolic. These results support the hypothesis that ACAT is an allosteric enzyme regulated by cholesterol. |