| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Association between sympathetic activity and the atherogenic serum cholesterol fraction Weidmann, P., D. C. Schohn, et al. (1990), Klin Wochenschr 68(5): 269-76. Abstract: A possible modulating influence of noradrenergic activity on serum lipoproteins was assessed under placebo conditions and following 4 weeks of sympathetic neurone blockade with debrisoquine in 9 normal subjects, 11 patients with mild essential hypertension, 9 normotensive, and 9 hypertensive hemodialysis patients. Plasma norepinephrine (NE) did not differ significantly among groups on placebo and was consistently reduced (P less than 0.05-0.001) by sympathetic blockade. The latter also decreased (P less than 0.05-0.001) plasma total cholesterol (C) as well as low and very low density lipoprotein cholesterol (LDL + VLDL-C) in the three patient groups. In the two dialysis groups, basal levels of plasma triglycerides (Tg) were increased and high density lipoprotein cholesterol (HDL-C) was diminished (P less than 0.01-0.001); sympathetic blockade lowered Tg and raised HDL-C (P less than 0.01-0.001). In normal subjects, sympathetic blockade did not significantly modify plasma lipoproteins. In the three patient groups, significant correlations (r = 0.62 - 0.88; P less than 0.05 - less than 0.001) existed between (a) basal plasma NE and total C or LDL + VLDL-C and (b) debrisoquine-induced changes in NE and changes in total LDL + VLDL-C. These findings suggest that in essential hypertension as well as in hemodialysis patients, the atherogenic C fraction, represented by LDL + VLDL-C, may be modulated by the noradrenergic activity. |
| Association between the cholesteryl ester transfer protein TaqI-detectable B polymorphism and low high-density lipoprotein cholesterol concentration in Saudis Al-Daghri, N. M., O. Al-Attas, et al. (2003), Clin Sci (Lond) 105(4): 467-72. Abstract: Plasma concentrations of HDL (high-density lipoprotein) cholesterol are low in the Saudi Arabian population. A B polymorphism at the CETP (cholesteryl ester protein transfer) locus that is detectable with the restriction enzyme Taq I is a genetic determinant of the plasma HDL cholesterol concentration. We assessed the relationship between the Taq I B CETP polymorphism and lipid and apolipoprotein concentrations in a study sample of 335 Saudi residents. The Taq I B1 and B2 allele frequencies were 0.54 and 0.46 respectively, similar to those in other populations. HDL cholesterol levels in B2B2 homozygotes were significantly higher than in B1B1 homozygotes 1.01 (0.3) compared with 0.92 (0.2) mmol/l; mean (S.D.); P=0.03. There was also a significant difference between the B2B2 and B1B1 homozygotes with regard to apolipoprotein AI concentration 123.6 (16.4) compared with 113.7 (13.9) mg/dl; P=0.04. This genetic variation was independent of metabolic risk factors known to influence HDL cholesterol levels. The allele frequency of the Taq I B CETP polymorphism and its relatively modest impact on HDL cholesterol concentrations argue against an important role for this allele, or for strongly linked loci, in determining the low levels of HDL cholesterol seen in the Saudi population. |
| Association between thyroid dysfunction and total cholesterol level in an older biracial population: the health, aging and body composition study Kanaya, A. M., F. Harris, et al. (2002), Arch Intern Med 162(7): 773-9. Abstract: BACKGROUND: Thyroid dysfunction increases with age. Less is known about the prevalence of thyroid disease in older black adults and whether an association between thyroid function and serum cholesterol level exists, as in older white adults. METHODS: A cross-sectional study of 2799 well functioning white and black participants, aged 70 to 79 years, were recruited for a population-based study. Participants underwent thyrotropin, free thyroxine, and total cholesterol testing; a medical history; and physical measurements. RESULTS: Among the entire cohort, 94% were euthyroid based on biochemical testing results. Approximately 10% were taking thyroid hormones. Subclinical hypothyroidism was the most prevalent disorder (3.1% of all participants not taking thyroid hormones), but black men and women had lower rates of this condition than white men and women. After excluding those taking thyroid or lipid medication and adjusting for potential confounders, an elevated thyrotropin level (>5.5 mIU/mL) was associated with a 9 mg/dL (0.23 mmol/L) higher cholesterol level, and a suppressed thyrotropin level (<0.35 mIU/mL) was associated with a 19 mg/dL (0.49 mmol/L) lower cholesterol level. CONCLUSION: Healthy community-dwelling older black adults have a lower prevalence of thyroid dysfunction compared with older white adults, but the association between increased thyrotropin and increased cholesterol levels is similar in both races. |
| Association between total cholesterol and plasma thromboxane B2 in human adults Peto, J., K. Mihai, et al. (1992), Agents Actions Suppl 37: 210-4. Abstract: Apparently healthy adults were examined for their lipid and thromboxane parameters. The correlation between the levels of total cholesterol in serum and thromboxane B2/TXB2/ in plasma was strong mainly in men (p less than 0.01). However, the association between atherogenic index /AI/ and TXB2 levels tended to be higher in women. The authors suggest that, in healthy adults, elevated cholesterol levels coexist with abnormalities in thromboxane metabolism. |
| Association between total cholesterol and thromboxane B2 levels in offspring of parents suffering from premature coronary artery disease Mihai, K., J. Peto, et al. (1992), Agents Actions Suppl 37: 190-6. Abstract: Relationship between plasma thromboxane B2 concentration and serum total cholesterol level was studied in 129 healthy 3 to 18 years old children, 77 girls and 52 boys, without any family history of premature coronary artery disease and in 181 offspring, 105 girls and 76 boys, of parents suffering from acute myocardial infarction before the age of 45. It was identified an enhancement in serum total cholesterol level of endangered children, and an elevated release of thromboxane A2 in affected girls. A significant negative correlation was found between serum total cholesterol concentration and plasma thromboxane B2 level in healthy girls. However, there was no correlation between serum total cholesterol level and plasma thromboxane B2 concentration in the children whose parents had premature coronary artery disease. It appears, from our results, that this in an alteration of thromboxane A2 release of platelets in children of families with high risk of cardiovascular diseases. |
| Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels Karvonen, M. K., U. Pesonen, et al. (1998), Nat Med 4(12): 1434-7. Abstract: High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects. |
| Association of a mast cell chymase gene variant with HDL cholesterol, but not with blood pressure in the Ohasama study Fukuda, M., T. Ohkubo, et al. (2002), Hypertens Res 25(2): 179-84. Abstract: Two enzymes, chymase and angiotensin converting enzyme (ACE), are involved in the production of angiotensin II. Our previous study revealed the male-specific effect of the ACE DD genotype on the risk for hypertension, but the genetic role of chymase remains unclear. In the present study, we report the results of an association study involving 1,046 subjects recruited from a general population in Ohasama, a rural community in the northern part of Japan. In addition to casual blood pressure (casual BP) measurement, home BP measurements were obtained from all participants. There were no differences in either home or casual BP values according to G3255A polymorphism of the mast cell chymase gene (MCC). HDL cholesterol level was significantly higher among carriers of the A3255 allele (p<0.04). After adjustment for confounding factors, the A3255 allele was still shown to have an effect on HDL cholesterol metabolism (p<0.03). Multiple regression analysis showed that MCC polymorphism was significantly and independently related to serum HDL cholesterol level. In conclusion, G3255A polymorphism of MCC is not directly associated with blood pressure but may modulate the prevalence of hypertensive complications via alteration of lipid metabolism. |
| Association of angiographically detected coronary artery disease with low levels of high-density lipoprotein cholesterol and systemic hypertension French, J. K., J. M. Elliott, et al. (1993), Am J Cardiol 71(7): 505-10. Abstract: The prevalence of risk factors for atherosclerosis in 488 consecutive patients undergoing cardiac catheterization for the investigation of chest pain was compared with that in 868 subjects from a population sample. The presence and severity of angiographic coronary artery disease (CAD) (defined as mean diameter stenosis > 50%), total and high-density lipoprotein (HDL) cholesterol, triglycerides, history of systemic hypertension, smoking, diabetes mellitus, family history and drug therapy were assessed. Low HDL cholesterol (< 0.9 mmol/liter 35 mg/dl) was more prevalent in patients with CAD than in the population sample in both men (44% 95% confidence interval 38 to 48 vs 21% 12 to 28; p < 0.01) and women (12% 9 to 15 vs 1% 0 to 3; p < 0.01). There were no differences in total cholesterol levels between these 2 groups. Total:HDL cholesterol ratios were significantly greater in patients with CAD. History of systemic hypertension was more prevalent in both men and women with CAD than in the population sample (47% 37 to 57 vs 20% 16 to 25 for men, and 31% 26 to 36 vs 21% 17 to 26 for women; p < 0.01). The prevalence of other risk factors was not significantly different between the 2 groups. In patients with CAD, the severity of disease was inversely correlated with levels of HDL cholesterol in both men and women (p < 0.01), and positively correlated with total cholesterol in men aged < 55 years (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS) |
| Association of annexin 2 with recycling endosomes requires either calcium- or cholesterol-stabilized membrane domains Zeuschner, D., W. Stoorvogel, et al. (2001), Eur J Cell Biol 80(8): 499-507. Abstract: Annexin 2 is a Ca2+- and phospholipid-binding protein previously identified on endosomal membranes and the plasma membrane. Inferred from this location and its stimulatory effect on membrane transport annexin 2 has been proposed to play a role in the structural organization and dynamics of endosomal membranes. Validation of this view requires a detailed analysis of the distribution of annexin 2 over the endosomal compartment and a characterization of the parameters governing this distribution. Towards this end we have devised an immunoisolation protocol to purify annexin 2-positive membrane vesicles from subcellular fractions of BHK cells containing early endosomes. We show that this approach leads to the isolation of intact endosomal vesicles containing internalized fluid-phase marker and that the immunoisolated membranes are positive for the transferrin receptor and Rab4 but not for the early endosomal antigen EEA1. A distinct and non-uniform distribution of annexin 2 over the early endosomal compartment is also observed in immunoelectron microscopy analyses of whole-mount specimens of BHK cells. Annexin 2 antibodies labeled transferrin receptor-containing tubular early endosomal structures, but not EEAl-positive endosomal vacuoles. We also observed that the Ca2+-independent association of annexin 2 with endosomal membranes was disrupted by the cholesterol-binding glycerid saponin, while Ca2+ could trigger annexin 2 binding to saponin-treated endosomal membranes. Thus, either Ca2+- or cholesterol-stabilized membrane domains are required for the binding of annexin 2 to endosomes suggesting that both factors may regulate this interaction. |
| Association of apolipoprotein B gene variants with plasma apoB and low density lipoprotein (LDL) cholesterol levels Deeb, S. S., R. A. Failor, et al. (1992), Hum Genet 88(4): 463-70. Abstract: The contribution of the variants of the apolipoprotein (apo) B locus to the total variance in plasma apoB and cholesterol levels was examined in four independent populations, two that were composed of normal controls (n = 77 and 85) and two with coronary heart disease (n = 115 and 159). A correlation between genotype at the apoB-XbaI locus and apoB levels was observed. The effects of the (+; presence of restriction site) and (-) alleles were to increase or decrease the apoB and cholesterol levels by approximately 3.5 mg/dl, respectively. None of the 274 individuals in the coronary heart disease (CHD) groups was found to be a carrier of the apoB allele Arg3500----Gln, previously shown to be associated with an apoB protein defective in binding to the low density lipoprotein receptor (LDL-R). No DNA sequence variants were found in the region encoding amino acid residues 3129-3532 within the putative LDL-R binding domain among 35 individuals with apoB levels above the 94th percentile (141 mg/dl). |
| Association of apolipoprotein genetic polymorphisms with plasma cholesterol in a Japanese rural population. The Shibata Study Zaman, M. M., S. Ikemoto, et al. (1997), Arterioscler Thromb Vasc Biol 17(12): 3495-504. Abstract: The association between apolipoprotein (apo) genetic polymorphisms and lipid phenotypes remains to be determined because such studies have reported contradictory results. We have measured plasma total cholesterol (TC) and HDL cholesterol (HDL-C) in a cross-sectional sample of 1328 (462 men and 866 women) Japanese (aged 40 to 80 years) and analyzed their DNA for the following genotypes: apoA1-C3 Msp I and Sst I sites; apoB signal peptide insertion/deletion, Xba I site and 3' variable number of tandem repeats (VNTR); and apoE. Using multivariate analyses (ANOVA) we found that (1) the polymorphisms of apoA1-C3 and apoB genes are not significantly associated with TC or HDL-C and (2) the polymorphism of the apoE gene is significantly related with TC and the TC:HDL-C ratio. The epsilon 2 carriers have lower levels of TC and a lower TC:HDL-C ratio, epsilon 3 carriers have intermediate levels, and epsilon 4 carriers have higher levels. These findings held whether sexes were analyzed separately or together. Although an opposite trend in HDL-C levels was observed, it did not reach the level of statistical significance. Multiple regression analyses have shown that apoE polymorphism accounts for about 2.3% of the variation in TC and TC:HDL-C ratio irrespective of sex. When the subjects are divided into two groups according to their age (< or = 59 and > or = 60 years old), the effect of apoE alleles on serum cholesterols appears to be diluted in the younger age group whereas it appears to be accentuated in the older group for both sexes. Our findings suggest that among the apo genetic polymorphisms examined, the apoE gene may be considered as a possible candidate for the "high-risk" strategy of atherosclerosis prevention in the Japanese population. |
| Association of blood pressure variability with induction of atherosclerosis in cholesterol-fed rats Sasaki, S., Y. Yoneda, et al. (1994), Am J Hypertens 7(5): 453-9. Abstract: The influence of increased lability of blood pressure on the development of aortic atherosclerosis was examined. Because sinoaortic denervation (SAD) produced increased lability of blood pressure without blood pressure elevation, the development of atheromatous plaque was examined in SAD rats. These rats were fed a high-cholesterol diet and were denuded of endothelium so that development of atherosclerosis was accelerated. Five groups of male Wistar rats were used: A) controls, B) high-cholesterol diet (HC), C) HC+denudation (DN), D) HC+DN+renal artery clipping (2K1C), and E) HC+DN+sinoaortic denervation (SAD). Denudation was accomplished by scraping the aortic lumen with a balloon catheter, and hypertension was induced by clipping the left renal artery. After recording blood pressure and heart rate for 6 weeks, the rats were killed, blood samples were collected, and thoracic aortas were removed for pathologic examination. All the groups of rats fed a high-cholesterol diet developed marked hypercholesterolemia and hypotriglyceridemia. High-cholesterol diet alone could not induce aortic atherosclerosis, whereas aorta of HC+DN rats showed slight intimal thickening with smooth muscle cell proliferation. On the other hand, aorta of HC+DN + 2K1C rats showed marked atheromatous plaque with prominent cellular proliferation, and aorta of SAD rats also showed mild to moderate atheromatous plaque. Accordingly, we concluded that increased variability in circadian blood pressure per se, as well as hypertension, could induce aortic atherosclerosis in the hypercholesterolemic and endothelium-denuded rats. |
| Association of cholesterol levels and occurrence of angiographically detectable endothelial disruption during coronary angioplasty Rubboli, A., D. E. Euler, et al. (2003), Clin Cardiol 26(7): 336-40. Abstract: BACKGROUND: Disruption of the atherosclerotic plaque is a common feature of both acute coronary syndromes and balloon dilatation of coronary artery stenoses. HYPOTHESIS: The study was undertaken to evaluate whether the known association of cholesterol levels and acute coronary syndromes also exists for the occurrence of angiographically detectable endothelial disruption (ED) following coronary angioplasty. METHODS: For this purpose, we examined 79 consecutive patients (men/women 58/21; mean age: 62 +/- 11 years), with a noncalcified, de novo, significant stenosis in a single native coronary artery, undergoing elective coronary intervention because of stable effort angina. Coronary angioplasty was performed using regular balloon catheters, aiming for a balloon/ artery ratio of 1, with stent implantation allowed only provisionally. Following balloon dilatation, patients were divided into two groups according to the presence or absence of angiographically detectable ED. RESULTS: Endothelial disruption occurred in 28 patients (35%). The two groups with and without ED were comparable with respect to clinical, angiographic, and procedural parameters. A history of hypercholesterolemia was significantly more frequent in patients with ED (93 vs. 2%; p < 0.001). Total and low-density lipoprotein (LDL) cholesterol levels were significantly higher in the group with ED (230.1 +/- 46.5 vs. 204.4 +/- 30.2 mg/dl, p < 0.05; and 150.6 +/- 39.2 vs. 125.8 +/- 26 mg/dl, p < 0.03, respectively). A cut-off value of LDL cholesterol > or = 135 mg/dl identified patients at higher risk of developing ED. CONCLUSION: High cholesterol levels appear to favor the occurrence of ED during coronary angioplasty. Aggressive lipid-lowering therapy and a more careful procedural approach may be warranted in patients with hypercholesterolemia undergoing coronary interventions in order to decrease the occurrence of ED and the associated clinical (acute ischemia) and procedural (stent implantation) consequences. |
| Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community Bellamy, M. F., P. A. Pellikka, et al. (2002), J Am Coll Cardiol 40(10): 1723-30. Abstract: OBJECTIVES: This study was designed to analyze the association among cholesterol levels, lipid-lowering treatment, and progression of aortic stenosis (AS) in the community. BACKGROUND: Aortic stenosis is a progressive disease for which there is no known medical treatment to prevent or slow progression. Despite plausible pathologic mechanisms linking hypercholesterolemia to AS progression, clinical studies have been inconsistent and affected by referral bias, and the role of lipid-lowering therapy is uncertain. METHODS: We determined the association between blood cholesterol levels and progression of native AS (assessed by Doppler echocardiography at baseline and at least six months later; mean interval, 3.7 +/- 2.3 years) in a community-based study of 156 patients (age 77 +/- 12 years; 90 men). Thirty-eight patients received statin treatment during follow-up. RESULTS: In untreated subjects, mean gradient increased from 22 +/- 12 mm Hg to 39 +/- 19 mm Hg, and aortic valve area (AVA) decreased from 1.20 +/- 0.35 cm(2) to 0.91 +/- 0.33 cm(2) (both p < 0.001). The annualized change in AVA was -0.09 +/- 0.17 cm(2)/year (-7% +/- 13%/year). Neither total cholesterol (r = -0.01, p = 0.92) nor low-density lipoprotein cholesterol (r = 0.01; p = 0.88) showed a significant correlation to AS progression. Nevertheless, progression of AS was slower in patients receiving statins compared with untreated patients (decrease in AVA -3 +/- 10% vs. -7 +/- 13% per year, respectively; p = 0.04), even when adjusted for age, gender, cholesterol, and baseline valve area (p = 0.04). The association of statin treatment with slower progression was confirmed when analysis was restricted to patients coming for a systematic follow-up (p=0.02). The odds ratio of AS progression with statin treatment was 0.46 (95% confidence interval, 0.21 to 0.96). CONCLUSIONS: In the community, progression of AS shows no trend of association with cholesterol levels. Statin treatment, however, is associated with slower progression, suggesting that the effects of statin treatment on progression of AS should be pursued with appropriate clinical trials. |
| Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups Tirschwell, D. L., N. L. Smith, et al. (2004), Neurology 63(10): 1868-75. Abstract: OBJECTIVE: To perform a health maintenance organization-based case-control study to evaluate the association of total and high density lipoprotein (HDL) cholesterol with the risk of stroke subtypes and in patient subgroups. METHODS: Cases had a confirmed incident ischemic stroke (n = 1,242) or hemorrhagic stroke (n = 313). Controls (n = 6,455) were identified in a companion myocardial infarction study. Risk of stroke was modeled using logistic regression. RESULTS: The highest total cholesterol quintile was associated with an increased risk of ischemic stroke compared to the lowest quintile (OR = 1.6, 95% CI 1.3 to 2.0) with the strongest subtype associations for atherosclerotic stroke (OR = 3.2) and lacunar stroke (OR = 2.4). The highest HDL cholesterol quintile was associated with a decreased risk of ischemic stroke compared to the lowest quintile (OR = 0.8, CI 0.6 to 1.0). Subgroup analyses suggested that the total cholesterol association was more important for patients < 66 years of age and those with HDL < 50 mg/dL; the HDL association was more important for patients without diabetes or atrial fibrillation. The second through fourth total cholesterol quintiles were associated with a decreased risk of hemorrhagic stroke compared to the lowest quintile (OR = 0.7, CI 0.5 to 1.0). CONCLUSIONS: Higher total and lower HDL cholesterol levels were associated with increased risk of ischemic stroke, especially certain stroke subtypes and patient subgroups. The lowest levels of total cholesterol were associated with an increased risk of all hemorrhagic strokes. |
| Association of dehydroepiandrosterone sulfate with serum HDL-cholesterol concentrations in post-menopausal Japanese women Nagata, C., N. Takatsuka, et al. (1998), Maturitas 31(1): 21-7. Abstract: OBJECTIVES: Positive association between serum dehydroepiandrosterone sulfate (DHEAS) and high-density lipoprotein (HDL) cholesterol has been observed in men but not women. We aimed to examine the cross-sectional relationships of DHEAS, estradiol (E2), and sex hormone-binding globulin (SHBG) to serum lipid concentrations in post-menopausal Japanese women. METHODS: A total of 56 post-menopausal Japanese women were derived from female residents in Takayama City in Japan. The information on body size, disease history, reproductive history, diet, and physical activity were obtained by a self-administered questionnaire. RESULTS: DHEAS was significantly and positively correlated with HDL-cholesterol after controlling for age and body mass index (BMI) (r = 0.28). There was no correlation between DHEAS and total-cholesterol (r = -0.02). E2 was not significantly correlated with total- and HDL-cholesterol and triglyceride. However, SHBG-unbound E2 was significantly positively correlated with HDL-cholesterol (r = 0.34) and negatively correlated with triglyceride (r = -0.27) after controlling for age and BMI. SHBG was negatively correlated with triglyceride, although the correlation was not statistically significant (r = -0.22). CONCLUSION: These data suggest favorable effect of DHEAS as well as E2 and SHBG on lipid profile in Japanese post-menopausal women. |
| Association of DNA-haplotypes in the human LDL-receptor gene with normal serum cholesterol levels Schuster, H., S. Humphries, et al. (1990), Clin Genet 38(6): 401-9. Abstract: For the low density lipoprotein receptor (LDLR), many mutations have been characterized which identify this gene as one with an important role in lipid metabolism in patients with familial hypercholesterolemia (FH). Genetic heterogeneity at this locus raises the possibility that the LDLR may also contribute to variation in cholesterol levels in the normocholesterolemic population. We have determined genotypes at the LDLR locus using restriction fragment length polymorphisms (RFLPs) detected with the enzymes StuI, ApalI, PvuII and NcoI in 324 normocholesterolemic individuals from Germany. A significant association (p less than 0.01) was detected between the cutting site for the PvuII RFLP and lower cholesterol levels, and variation associated with this polymorphism explains 3% of the sample variance in cholesterol levels. In family studies we have determined four-RFLP haplotypes of 148 independent LDLR genes and have observed 9 haplotypes in the population. Three of these haplotypes containing the cutting site for PvuII are associated with a reduction in plasma LDL-cholesterol levels. Phylogenetic analysis indicates that these three haplotypes are related by evolutionary history, and this suggests that a single functionally important sequence change in the LDLR explains our observations. Our data confirm other reports and strongly suggest that the LDLR locus may be one of those genes involved in determining serum cholesterol levels in the normal population. |
| Association of ethanol with lipid membranes containing cholesterol, sphingomyelin and ganglioside: a titration calorimetry study Trandum, C., P. Westh, et al. (1999), Biochim Biophys Acta 1420(1-2): 179-88. Abstract: The association of ethanol at physiologically relevant concentrations with lipid bilayers of different lipid composition has been investigated by use of isothermal titration calorimetry (ITC). The liposomes examined were composed of combinations of lipids commonly found in neural cell membranes: dimyristoyl phosphatidylcholine (DMPC), ganglioside (GM(1)), sphingomyelin and cholesterol. The calorimetric results show that the interaction of ethanol with fluid lipid bilayers is endothermic and strongly dependent on the lipid composition of the liposomes. The data have been used to estimate partitioning coefficients for ethanol into the fluid lipid bilayer phase and the results are discussed in terms of the thermodynamics of partitioning. The presence of 10 mol% sphingomyelin or ganglioside in DMPC liposomes enhances the partitioning coefficient by a factor of 3. Correspondingly, cholesterol (30 mol%) reduces the partitioning coefficient by a factor of 3. This connection between lipid composition and partitioning coefficient correlates with in vivo observations. Comparison of the data with the molecular structure of the lipid molecules suggests that ethanol partitioning is highly sensitive to changes in the lipid backbone (glycerol or ceramide) while it appears much less sensitive to the nature of the head group. |
| Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function Butchbach, M. E., G. Tian, et al. (2004), J Biol Chem 279(33): 34388-96. Abstract: In the present study, we investigated the role of membrane cholesterol in the function of glutamate transporters. Depletion of membrane cholesterol by methyl-beta-cyclodextrin resulted in reduced Na(+)-dependent glutamate uptake in primary cortical cultures. Glial glutamate transporter EAAT2-mediated uptake was more sensitive to this effect. Cell surface biotinylation and immunostaining experiments revealed that the loss of cholesterol significantly altered the trafficking of EAAT2 to the plasma membrane as well as their membrane distribution. These effects were also observed in neuronal glutamate transporter EAAT3 but to a lesser extent. Furthermore, the treatment of mouse brain plasma membrane vesicles with methyl-beta-cyclodextrin resulted in a significant reduction in glutamate uptake, suggesting that cholesterol depletion has a direct effect on the function of the glutamate transporters. Plasma membrane cholesterol is localized within discreet microdomains known as lipid rafts. Analyses of purified lipid raft microdomains revealed that a large portion of total EAAT2 and a minor portion of total EAAT1, EAAT3, and EAAT4 were associated with lipid rafts. Artificial aggregation of lipid rafts in vivo resulted in the formation of larger EAAT2-immunoreactive clusters on the cell surface. The purified lipid raft-associated fractions were capable of Na(+)-dependent glutamate uptake. Our data suggest that the glutamate transporters, especially EAAT2, are associated with cholesterol-rich lipid raft microdomains of the plasma membrane and that the association with these cholesterol-rich microdomains is important for excitatory amino acid transporter localization and function. |
| Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors Morabia, A., E. Cayanis, et al. (2003), Hum Mol Genet 12(21): 2733-43. Abstract: This study explored the genetic basis of the combination of extreme blood levels of HDL-C and LDL-C, a well-studied endophenotype for CVD, which has several attractive features as a target for genetic analysis: (1) the trait is moderately heritable; (2) non-genetic risk factors account for a significant but still limited portion of the phenotypic variance; (3) it is known to be moderated by a number of gene products. We exhaustively surveyed 11 candidate genes for allelic variation in a random population-based sample characterized for known CVD risk factors and blood lipid profiles. With the goal of generating specific etiological hypotheses, we compared two groups of subjects with extreme lipid phenotypes, from the same source population, using a case-control design. Cases (n=186) were subjects, within the total sample of 1708 people, who scored in the upper tertile of LDL-C and the lowest tertile of HDL-C, while controls (n=185) scored in the lowest tertile of LDL-C and the upper tertile of HDL-C. We used logistic regression and a four-tiered, systematic model building strategy with internal cross-validation and bootstrapping to investigate the relationships between the trait and 275 genetic variants in the presence of 10 non-genetic risk factors. Our results implicate a subset of nine genetic variants, spanning seven candidate genes, together with five environmental risk factors, in the etiology of extreme lipoprotein phenotypes. We propose a model involving these 14 genetic and non-genetic risk factors for evaluation in future independent studies. |