| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
| First Page | Previous Page | Next Page | Last Page |
| Limitations of the Friedewald formula for estimating low-density lipoprotein cholesterol in alcoholics with liver disease Matas, C., M. Cabre, et al. (1994), Clin Chem 40(3): 404-6. Abstract: The accuracy of the Friedewald formula in estimating low-density lipoprotein (LDL) cholesterol was investigated in 47 alcoholic patients with liver disease (21 minimal-change, 26 cirrhotic) by comparing the results with those obtained by sequential preparative ultracentrifugation. In 14% of subjects with minimal-change disease, the error in the estimated LDL cholesterol was 50% +/- 9% (mean +/- SD; range 40-59%) and was related to the degree of attendant hypertriglyceridemia (r = 0.98; P < 0.001). A similar degree of error was observed in patients with cirrhosis, despite the absence of hypertriglyceridemia; an abnormal VLDL cholesterol: triglyceride ratio was the contributory factor in the discrepancy. We conclude that, as is the case in other clinical pathologies in which abnormalities of lipoprotein composition have been described (e.g., diabetes), the Friedewald formula to estimate LDL cholesterol may be inappropriate in chronic alcoholics, particularly those in whom a degree of hepatic dysfunction may be suspected. |
| Limited proteolysis of high density lipoprotein abolishes its interaction with cell-surface binding sites that promote cholesterol efflux Mendez, A. J. and J. F. Oram (1997), Biochim Biophys Acta 1346(3): 285-99. Abstract: High-density lipoprotein (HDL) components remove cholesterol from cells by two independent mechanisms. Whereas HDL phospholipids pick up cholesterol that desorbs from the plasma membranes, HDL apolipoproteins appear to interact with cell-surface binding sites that target for removal pools of cellular cholesterol that feed into the cholesteryl ester cycle. Here we show that mild trypsin treatment of HDL almost completely abolishes this apolipoprotein-mediated cholesterol removal process. When HDL was treated with trypsin for various periods of time and then incubated with cholesterol-loaded fibroblasts, treatment for only 5 min reduced the ability of HDL to remove excess cholesterol from cellular pools that were accessible to esterification by the enzyme acyl CoA:cholesterol acyltransferase. This mild treatment digested less than 20% of HDL apolipoproteins and did not alter the lipid composition, size distribution, or electrophoretic mobility of the particles. Trypsin treatment of HDL for up to 1 h caused no further reduction in its ability to remove cellular cholesterol despite a greater than 2-fold increase in apolipoprotein digestion. Trypsin treatment of HDL also reduced its ability to deplete the cholesteryl ester content of sterol-laden macrophages. Promotion of cholesterol efflux from the plasma membrane by HDL phospholipids was unaffected by even extensive proteolysis. In parallel to the loss of cholesterol transport-stimulating activity, trypsin treatment of HDL for only 5 min nearly abolished its interaction with high-affinity binding sites on cholesterol-loaded fibroblasts. Reconstitution of trypsin-modified HDL with isolated apo A-I or apo A-II restored the cholesterol transport-stimulating activity of the particles. Thus a minor trypsin-labile fraction of HDL apolipoproteins is almost exclusively responsible for the apolipoprotein-dependent component of cholesterol efflux mediated by HDL particles. |
| Link between heart disease, cholesterol, and Alzheimer's disease: a review Sparks, D. L., T. A. Martin, et al. (2000), Microsc Res Tech 50(4): 287-90. Abstract: Increased prevalence of Alzheimer's disease-like beta-amyloid deposits in the neuropil and within neurons occurs in the brains of non-demented individuals with heart disease. Heart disease is a prevalent finding in Alzheimer's disease, and may be a forerunner to the dementing disorder. In the cholesterol-fed rabbit model of human coronary heart disease there is production and accumulation of beta-amyloid in the brain. This accumulation of beta-amyloid can be reversed by removing cholesterol from the rabbits' diet. In culture cells, a cholesterol challenge has been shown to increase production of beta-amyloid, and dramatic reductions of cholesterol produced by HMG Co-A reductase inhibitors decrease production of beta-amyloid. Increased beta-amyloid production is also produced by dietary cholesterol in a number of transgenic mouse models of Alzheimer's disease. Administration of HMG Co-A reductase inhibitors may block beta-amyloid production caused by dietary cholesterol in rabbits. Clinical trials testing the benefit of HMG Co-A reductase inhibitors in the treatment of Alzheimer's disease are underway. |
| Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations Wang, J., D. J. Freeman, et al. (1998), J Clin Invest 101(6): 1283-91. Abstract: Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population. |
| Linkage mapping of total cholesterol level in a young cohort via nonparametric regression Ghosh, S., S. Bertelsen, et al. (2003), BMC Genet 4 Suppl 1: S92. Abstract: BACKGROUND: Compared to model-based approaches, nonparametric methods for quantitative trait loci mapping are more robust to deviations in distributional assumptions. In this study, we modify a nonparametric regression method and the "contrast function"- based regression method to analyze total cholesterol level in the younger cohort (the offspring generation) of the Genetic Analysis Workshop 13 simulated data set. RESULTS: We obtained significant evidence of linkage near four of the six non-sex-specific genes in at least 30% of the replicates. CONCLUSIONS: The proposed nonparametric method seems to be a powerful robust alternative to distribution-based methods. |
| Linkage of high-density lipoprotein-cholesterol concentrations to a locus on chromosome 9p in Mexican Americans Arya, R., R. Duggirala, et al. (2002), Nat Genet 30(1): 102-5. Abstract: High-density lipoproteins (HDLs) are anti-atherogenic lipoproteins that have a major role in transporting cholesterol from peripheral tissues to the liver, where it is removed. Epidemiologic studies have shown that low levels of high-density lipoprotein-cholesterol (HDL-C) are associated with an increased incidence of coronary heart disease and an increased mortality rate, indicating a protective role of high concentrations of HDL-C against atherogenesis and the development of coronary heart disease. HDL-C level is influenced by several genetic and nongenetic factors. Nongenetic factors include smoking, which has been shown to decrease the HDL-C level. Exercise and alcohol have been shown to increase HDL-C levels. Decreased HDL-C is often associated with other coronary heart disease risk factors such as obesity, hyperinsulinemia and insulin resistance, hypertriglyceridemia and hypertension. Although several genes have been identified for rare forms of dyslipidemia, the genes accounting for major variation in HDL-C levels have yet to be identified. Using a multipoint variance components linkage approach, we found strong evidence of linkage (lod score=3.4; P=0.00004) of a quantitative trait locus (QTL) for HDL-C level to a genetic location between markers D9S925 and D9S741 on chromosome 9p in Mexican Americans. A replication study in an independent set of Mexican American families confirmed the existence of a QTL on chromosome 9p. |
| Linkage of the apo CIII microsatellite with isolated low high-density lipoprotein cholesterol Devlin, C. M., V. L. Prenger, et al. (1998), Hum Genet 102(3): 273-81. Abstract: To evaluate whether a highly polymorphic microsatellite region within intron 3 of the apolipoprotein (apo) CIII gene is linked to the isolated low HDL-C phenotype, we studied eight unrelated probands (mean HDL-C = 10+/-5 mg/dl) and 157 biological family members. After PCR amplification of genomic DNA and denaturing polyacrylamide gel electrophoresis, 26 alleles were identified in this microsatellite including 9 alleles heretofore unreported. Quantitative sib-pair linkage analysis demonstrated strong evidence of linkage between the isolated low HDL-C phenotype and the apo CIII microsatellite region (P = 0.007). The microsatellite was also linked to apo AI (P = 0.001), the primary apolipoprotein of HDL-C. Therefore, this highly polymorphic microsatellite region is a potentially important marker in the genetic evaluation of the isolated low HDL-C phenotype. |
| Linkage of the cholesterol 7alpha-hydroxylase gene and low-density lipoprotein cholesterol conditional on apolipoprotein E association: the National Heart, Lung, and Blood Institute Family Heart Study Lin, J. P., R. H. Myers, et al. (2005), Chin Med J (Engl) 118(5): 362-9. Abstract: BACKGROUND: Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7alpha-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. METHODS: Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. RESULTS: The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly. CONCLUSION: Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases. |
| Linkage study of the low-density lipoprotein-receptor gene and cholesterol levels in an Afrikaner family. Quantitative genetics and identification of a minor founder effect Brink, P. A., L. T. Brink, et al. (1990), S Afr Med J 77(6): 292-6. Abstract: Overlap of clinical and biochemical characteristics between hypercholesterolaemia in members of the general population and familial hypercholesterolaemic (FH) individuals may lead to misdiagnosis. Quantitative analysis of family data may circumvent this problem. A way of looking for an association between plasma cholesterol levels and restriction fragment length polymorphism markers (RFLP) on the low-density lipoprotein (LDL) receptor gene by using reference cholesterol distributions was explored. Linkage, with a logarithm of the odds (LOD) score of 6.8 at theta 0, was detected between cholesterol levels and the LDL receptor in an extended Afrikaner family. Two RFLP-haplotypes, one previously found in a majority of Afrikaner FH homozygotes, and a second, Stu I-, BstE II+, Pvu II+, Nco I+, were associated with high cholesterol levels in this pedigree. |
| Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model Ludewig, B., S. Freigang, et al. (2000), Proc Natl Acad Sci U S A 97(23): 12752-7. Abstract: Arterial inflammatory responses are thought to be a significant component of atherosclerotic disease. We describe here, using a transgenic approach, the mutual perpetuation of immune-mediated arterial inflammation and cholesterol-induced atherosclerosis. Mice expressing the bacterial transgene beta-galactosidase exclusively in cardiomyocytes and in smooth muscle cells in lung arteries and the aorta (SM-LacZ), and hypercholesterolemic apolipoprotein E-deficient SM-LacZ mice (SM-LacZ/apoE(-/-)) developed myocarditis and arteritis after immunization with dendritic cells presenting a beta-galactosidase-derived immunogenic peptide. Hypercholesterolemia amplified acute arteritis and perpetuated chronic arterial inflammation in SM-LacZ/apoE(-/-) mice, but had no major impact on acute myocarditis or the subsequent development of dilated cardiomyopathy. Conversely, arteritis significantly accelerated cholesterol-induced atherosclerosis. Taken together, these data demonstrate that the linkage of immune-mediated arteritis and hypercholesterolemia favors initiation and maintenance of atherosclerotic lesion formation. Therapeutic strategies to prevent or disrupt such self-perpetuating vicious circles may be crucial for the successful treatment of atherosclerosis. |
| Links between body mass index, total body fat, cholesterol, high-density lipoprotein, and insulin sensitivity in patients with obesity related to depression, anger, and anxiety Laederach-Hofmann, K., S. Kupferschmid, et al. (2002), Int J Eat Disord 32(1): 58-71. Abstract: OBJECTIVE: Define links between psychosocial parameters and metabolic variables in obese females before and after a low-calorie diet. METHOD: Nine female obese patients (age 36.1 +/- 7.1 years, body mass index BMI > 30 kg/m2) were investigated before and after a 6-week low-calorie diet accompanied by behavior therapy. Blood lipids, insulin sensitivity (Bergman protocol), fat distribution (by dual-energy X-ray absorptiometry DEXA), as well as psychological parameters such as depression, anger, anxiety, symptom load, and well-being, were assessed before and after the dieting period. RESULTS: The females lost 9.6 +/- 2.8 kg (p <.0001) of body weight, their BMI was reduced by 3.5 +/- 0.3 kg/m2 (p <.0001), and insulin sensitivity increased from 3.0 +/- 1.8 to 4.3 +/- 1.5 mg/kg (p =.05). Their abdominal fat content decreased from 22.3 +/- 5.5 to 18.9 +/- 4.5 kg (p <.0001). In parallel, psychological parameters such as irritability (p <.05) and cognitive control (p <.0001) increased, whereas feelings of hunger (p <.05), externality (p <.05), interpersonal sensitivity (p <.01), paranoid ideation (p <.05), psychoticism (p <.01), and global severity index (p <.01) decreased. Prospectively, differences in body fat (percent) were correlated to nervousness (p <.05). Waist-to-hip ratio (WHR) differences were significantly correlated to sociability (p <.05) and inversely to emotional instability (p <.05), whereas emotional instability was inversely correlated to differences in insulin sensitivity (p <.01). DISCUSSION: Weight reduction may lead to better somatic risk factor control. Women with more nervousness and better sociability at the beginning of a diet period may lose more weight than others. |
| Linoleic acid lowers LDL cholesterol without a proportionate displacement of saturated fatty acid Rassias, G., M. Kestin, et al. (1991), Eur J Clin Nutr 45(6): 315-20. Abstract: We tested the specificity of the plasma cholesterol-lowering effect of linoleic acid in a comparison of linoleate-rich and saturated fatty acid-rich foods. Twelve mildly hypercholesterolemic men and women ate the two diets for three weeks each in a random cross-over design, after a two-week baseline period. A linoleic acid-rich supplement was added to the baseline diet so that the saturated and monounsaturated fatty acid content did not change significantly. Despite the consequent increase in total fat intake, the linoleate-rich diet (23 per cent energy from polyunsaturated fatty acids) significantly lowered plasma total and low-density lipoprotein (LDL) cholesterol (-8 per cent and -14 per cent respectively), while high-density lipoprotein (HDL) cholesterol rose 8 per cent. The direction of these changes was similar in all 12 subjects. Compared with a supplement that raised dietary saturated fatty acids to 30 per cent energy, the linoleate acid-rich diet gave lower total cholesterol (-14 per cent), LDL cholesterol (-18 per cent) and HDL cholesterol (-12 per cent) concentrations. Linoleic acid lowers LDL cholesterol even when saturated fatty acids are not significantly displaced and substantially more when there is such displacement. |
| Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDL-Atherosclerosis Treatment Study Design Brown, B. G., X. Q. Zhao, et al. (1998), Can J Cardiol 14 Suppl A: 6A-13A. Abstract: Evidence supports the idea that substantial benefits may derive from treatments that increase high density lipoprotein (HDL) cholesterol (HDL-C), apolipoprotein (apo) A-I, HDL2 (or 2b) or the size of HDL particles with, or without, apo A-II. HDL3 appears to be neutral in terms of coronary artery disease risk, and apo A-II appears to be adverse. Because HDL particles serve as antioxidants in vitro, the hypothesis that low HDL-C reflects an antioxidant deficiency state appears tenable. Based on these observations, a three-year angiographic study was proposed and received funding. Enrollment began in January 1995 and was completed in January 1997. |
| Lipid and cholesterol trafficking in NPC Mukherjee, S. and F. R. Maxfield (2004), Biochim Biophys Acta 1685(1-3): 28-37. Abstract: Niemann-Pick type C, or NPC for short, is an early childhood disease exhibiting progressive neurological degeneration, associated with hepatosplenomegaly in some cases. The disease, at the cellular level, is a result of improper trafficking of lipids such as cholesterol and glycosphingolipids (GSLs) to lysosome-like storage organelles (LSOs), which become engorged with these lipids. It is believed that the initial defect in trafficking, whether of cholesterol or a GSL, results in an eventual traffic jam in these LSOs. This leads to the retention of not only other lipids, but also of transmembrane proteins that transiently associate with the late endosomes (LE) in normal cells, on their way to other cellular destinations such as the trans-Golgi network (TGN). In this review, we discuss the biophysical properties of lipids and cholesterol that might determine their intracellular itineraries, and how these itineraries are altered in NPC cells, which have defects in the proteins NPC1 or NPC2. We also discuss some potential therapeutic directions being suggested by recent research. |
| Lipid- and lipoprotein-cholesterol levels in the first 8 months of low-weight (less than or equal to 1500 g) premature infants Decsi, T., D. Molnar, et al. (1991), Orv Hetil 132(17): 907-10. Abstract: Lipid levels were determined in 30 low birthweight (less than or equal to 1500 g) preterm infants (birthweight: 1122 +/- 192 g, gestational age: 29,0 +/- 1,7 weeks, mean +/- SD) on the 1st, 14th, 28th, 42nd and 56th days of life. Triglyceride and cholesterol were measured by a Boehringer kit, while HDL-cholesterol and its subfractions by microprecipitation methods. Both triglyceride and cholesterol levels increased significantly from the 1st to the 14th and from the 14th to the 28th days. VLDL + LDL-cholesterol level increased significantly by the 14th day, while HDL-cholesterol level by the 28th day. From the 1st to the 14th day the increment of cholesterol levels was significantly higher in breast milk-fed newborns (n = 18) than in those receiving formula (n = 12). Consequently, on the 14th, 28th and 42nd days cholesterol levels were significantly higher in breast milk-fed newborns than in those receiving formula. By the age of two months, however, the difference diminished. |
| Lipid apheresis: the only therapeutic option for a very small group of cardiovascular patients with high low-density lipoprotein cholesterol or lipopoprotein(a) blood concentrations Schwandt, P. (2003), Ther Apher Dial 7(3): 283-4. |
| Lipid bilayer and water proton magnetization transfer: effect of cholesterol Fralix, T. A., T. L. Ceckler, et al. (1991), Magn Reson Med 18(1): 214-23. Abstract: Magnetization transfer between macromolecules and water can be a significant factor contributing to tissue water 1H relaxation. Using saturation transfer techniques, the degree of magnetization transfer between the macromolecular matrix and bulk water 1H can be directly measured and magnetization transfer contrast (MTC) can be generated in MR images. A significant degree of MTC has been observed in tissues with high plasma membrane content such as kidney and brain. The purpose of this study was to establish whether lipid bilayers, as models for cell membranes, could exchange magnetization with the water solvent and whether this effect could contribute to MTC observed in intact tissues. Magnetization transfer was measured in aqueous dispersions of egg phosphatidylcholine (EPC) in the presence and absence of cholesterol. It was found that neither EPC bilayers nor cholesterol by themselves significantly exchanged magnetization with bulk water 1H. However, as the concentration of cholesterol was increased, the pseudo-first-order magnetization exchange rate increased to a maximum value of approximately 1 s-1. The cholesterol-induced 1H magnetization exchange may be related either to longer correlation times of the lipid or to an increase in the number of water molecules associated with the bilayer. These results indicate that EPC-cholesterol bilayers exchange 1H magnetization with bulk water. These results are consistent with lipid bilayer contributions to bulk water relaxation and MTC in intact biological tissues. |
| Lipid binding to amyloid beta-peptide aggregates: preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids Avdulov, N. A., S. V. Chochina, et al. (1997), J Neurochem 69(4): 1746-52. Abstract: Amyloid beta-peptide (A beta) aggregates are one of the key neuropathological characteristics of Alzheimer's disease. A beta belongs to a group of proteins that aggregate and form beta-sheets, and some of these proteins bind cholesterol and other lipids. The purpose of the experiments reported here was to determine if cholesterol, fatty acids, and phosphatidylcholine (PC) would bind to A beta(1-40) and if such binding would be dependent on aggregation of A beta(1-40). Lipid binding was determined using fluorescent-labeled lipids. Incubation of A beta(1-40) for 0, 1, 3, 6, 21, and 24 h resulted in aggregation of the peptide with formation of dimers, trimers (1-24 h), and polymers (6-24 h) as determined by sodium dodecyl sulfate-gel electrophoresis. No change in the fluorescence of the lipids was observed when lipids were added to A beta(1-40) that had been incubated for 0, 1, or 3 h. However, the fluorescence intensities of cholesterol, saturated fatty acids, and PC were significantly increased (p < 0.0001) when added to A beta(1-40) that had been incubated for 6, 21, and 24 h in which A beta(1-40) polymers were detected. The binding affinity of cholesterol to A beta(1-40) polymers (K(D) of 3.24 +/- 0.315 x 10(-9) M) was markedly higher as compared with the other lipids (stearic acid, 9.42 +/- 0.41 x 10(-8) M; PC, 7.07 +/- 0.12 x 10(-7) M). The results of this study indicate that A beta(1-40) polymers bind lipids and have a higher affinity for cholesterol than PC or saturated fatty acids. Aggregated A beta(1-40) may affect lipid transport between cells or remove specific lipids from membranes, and such effects could contribute to neuronal dysfunction. |
| Lipid composition of mononuclear cell membranes and serum from persons with high or low levels of serum HDL cholesterol Eggesbo, J. B., T. A. Hagve, et al. (1996), Scand J Clin Lab Invest 56(3): 199-210. Abstract: High density lipoprotein (HDL) levels have been shown to be inversely correlated with the incidence of coronary artery disease (CAD). Since we have previously found that peripheral blood mononuclear cells (PBMC) from persons with high (n = 10) or low HDL (n = 10) have different functional properties, we wanted to examine the PBMC membrane lipid composition and fluidity, as well as to characterize the serum lipoproteins in greater detail. In persons with high HDL, PBMC membrane phospholipids were higher, and the cholesterol/phospholipid (CH/PL) ratio lower than in persons with low HDL. Membrane cholesterol and phospholipids were positively correlated with serum HDL2. The fatty acid composition of membrane phospholipids, and membrane fluidity was similar. The median saturated/unsaturated fatty acid (SFA/UFA) ratio tended to be lower in PBMC membranes and in serum from persons with high HDL; however this was not statistically significant. In serum, total phospholipids and HDL2 components (cholesterol, phospholipids and protein) were higher in persons with high HDL, whereas non-esterified fatty acids (NEFA) and very low density lipoprotein (VLDL) components (triglycerides, cholesterol, phospholipids and protein) were lower. Furthermore, serum cholesterol esters and the cholesterol esters/free cholesterol (CE/FC) ratio was higher, and the atherogenic index, i.e. (apoB X (total cholesterol-HDLc)/apoA-I X HDLc, lower in persons with high HDL. These results demonstrate that PBMC from persons with high or low serum HDL have a different lipid composition presumably of importance for cell function, lipid transport and atherogenesis. |
| Lipid domains in the membrane: thermotropic properties of sphingomyelin vesicles containing GM1 ganglioside and cholesterol Ferraretto, A., M. Pitto, et al. (1997), Biochemistry 36(30): 9232-6. Abstract: The thermotropic behavior of palmitoylsphingomyelin vesicles containing GM1 ganglioside and cholesterol has been investigated by high-sensitivity differential scanning calorimetry. The thermograms exhibited by binary palmitoylsphingomyelin/GM1 mixtures are resolvable into two components. The relative contribution of the minor component, undetectable in the absence of ganglioside, to the total enthalpy and its transition temperature (>40 degrees C) increase with the concentration of the glycolipid embedded in the vesicles. These data suggest the occurrence of lateral phase separation and that more ordered, higher melting GM1 ganglioside-enriched domains are present within the sphingomyelin bilayer. Studies on binary sphingomyelin/cholesterol mixtures confirmed the known tendency of the sterol to decrease the total enthalpy of sphingomyelin, forming cholesterol-enriched domains. The thermograms exhibited by ternary sphingomyelin/ganglioside/cholesterol mixtures in variable proportions (up to 20% molar GM1 or Chol) displayed, on increasing the content of either the sterol or the ganglioside, features addressable to sphingomyelin/cholesterol (peaks centered at temperature 40 degrees C), respectively. This trend was confirmed by deconvolution analysis, showing that the thermograms are resolvable into components addressable to GM1-enriched and to cholesterol-enriched domains. Taken all together, the results show that the architectural features of sphingomyelin bilayers are strongly dependent on the presence of GM1 ganglioside and cholesterol, whose presence is leading to the formation of separate, GM1-enriched and cholesterol-enriched distinct domains. Ganglioside-sphingomyelin and sphingomyelin-cholesterol, together with mutual ganglioside-ganglioside, interactions could contribute to maintain a network of bonds extending to proteins, forming specialized membrane domains, such as caveolae, or others, whose experimental clues are the glycolipid-enriched detergent-insoluble fractions that can be isolated from cell membranes. |