| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Formation of spherical, reconstituted high density lipoproteins containing both apolipoproteins A-I and A-II is mediated by lecithin:cholesterol acyltransferase Clay, M. A., D. H. Pyle, et al. (2000), J Biol Chem 275(12): 9019-25. Abstract: Previous studies have provided detailed information on the formation of spherical high density lipoproteins (HDL) containing apolipoprotein (apo) A-I but no apoA-II (A-I HDL) by an lecithin:cholesterol acyltransferase (LCAT)-mediated process. In this study we have investigated the formation of spherical HDL containing both apoA-I and apoA-II (A-I/A-II HDL). Incubations were carried out containing discoidal A-I reconstituted HDL (rHDL), discoidal A-II rHDL, and low density lipoproteins in the absence or presence of LCAT. After the incubation, the rHDL were reisolated and subjected to immunoaffinity chromatography to determine whether A-I/A-II rHDL were formed. In the absence of LCAT, the majority of the rHDL remained as either A-I rHDL or A-II rHDL, with only a small amount of A-I/A-II rHDL present. By contrast, when LCAT was present, a substantial proportion of the reisolated rHDL were A-I/A-II rHDL. The identity of the particles was confirmed using apoA-I rocket electrophoresis. The formation of the A-I/A-II rHDL was influenced by the relative concentrations of the precursor discoidal A-I and A-II rHDL. The A-I/A-II rHDL included several populations of HDL-sized particles; the predominant population having a Stokes' diameter of 9.9 nm. The particles were spherical in shape and had an electrophoretic mobility slightly slower than that of the alpha-migrating HDL in human plasma. The apoA-I:apoA-II molar ratio of the A-I/A-II rHDL was 0.7:1. Their major lipid constituents were phospholipids, unesterified cholesterol, and cholesteryl esters. The results presented are consistent with LCAT promoting fusion of the A-I rHDL and A-II rHDL to form spherical A-I/A-II rHDL. We suggest that this process may be an important source of A-I/A-II HDL in human plasma. |
| Formulas predicting the percentile of serum cholesterol levels by age in adults Chung, S. J. (1990), Arch Pathol Lab Med 114(8): 869-75. Abstract: The data of the National Health and Nutrition Examination Survey comprehensively have shown that distributions of serum cholesterol levels in the US adult population are age and sex dependent. General formulas have been constructed on the basis of the data of the National Health and Nutrition Examination Survey to predict the adult percentile in the population for serum cholesterol levels by age. A mathematical model and a computer program previously published by the author were employed in this study. Analysis of the computer-assisted predicted and the National Health and Nutrition Examination Survey-reported percentiles indicated that the designed program for calculating the formula was accurate and reliable. The formulas can determine the relationship among adult age, serum cholesterol level, and population percentile. It has been reported that adult individuals tend to have persistently the same percentiles of their serum cholesterol levels in the population with increasing ages in the absence of cholesterol-altering intervention. The percentiles predicted by the formula may reflect the relative degrees of risk for coronary heart disease. This information on the percentile may have a preventive diagnostic value for the detection, evaluation, and treatment of patients with high cholesterol levels. The percentile may be used as a parameter of risk assessment for coronary heart disease for all adult ages and sexes. However, clarification of a probable relationship between high percentiles (like high cholesterol levels) and coronary heart disease, and justification of the use of percentiles as a risk parameter, must await further clinical investigation. |
| Formulation of liposomes with a soybean-derived sterylglucoside mixture and cholesterol for liver targeting Shimizu, K., Y. Maitani, et al. (1997), Biol Pharm Bull 20(8): 881-6. Abstract: In this study, we investigated a liposomal formulation of dipalmitoylphosphatidylcholine (DPPC) with a soybean-derived sterylglucoside mixture (SG) and cholesterol (Ch) for targeting the liver in mice. We found two distribution profiles of liposomes (reverse-phase evaporation vesicles, REV) in the liver depending on the concentration of Ch and SG in vivo; Ch tends to enhance liposomes containing 10 mol% SG accumulation in the liver, but to decrease those containing 20 mol% SG, and it prolongs the circulation in blood. Dicetylphosphate did not enhance liver targeting by liposomes with SG and Ch. More DPPC/SG/Ch-liposomes (6:1:3) were significantly taken up by cultivated hepatocytes than DPPC/SG/Ch-liposomes (6:0:4), suggesting a glucose residue. The optimal composition for the maximal liver targeting was a mixture of 0.2 micron DPPC/SG/Ch-liposomes (REV) at a molar ratio of 6:1:3. This composition of liposomes was distributed 3 times greater in hepatocytes than non-parenchymal cells 1 h after intravenous injection. |
| Fosinopril ameliorates exogenous cholesterol-induced incipient glomerular lesions in obese Zucker rats. Effects on eicosanoid secretion Higueruelo, S., M. Vaquero, et al. (1998), Nephrol Dial Transplant 13(9): 2227-33. Abstract: BACKGROUND: To date, the role of dietary cholesterol as a risk factor for some diabetic nephrophathy, such as mesangial expansion and glomerular lesions, is unknown. Controversy also exists regarding the effects of prostaglandin-induced changes in glomerular haemodynamics on the appearance of glomerulosclerosis. METHODS: We have used obese Zucker rats (OZRs) as a model of early nephrophathy to evaluate the effect of hypercholesterolaemic diet on glomerular prostaglandin secretion and on the development of glomerular lesions. Due to the role of angiotensin II (Ang II) in glomerular haemodynamics, we have also evaluated its effects on glomerular eicosanoid secretion. Furthermore, as it has been suggested recently by clinical studies that angiotensin-converting enzyme inhibitors (ACEIs) reduce serum lipids associated with proteinuria, we have also evaluated the effect of the ACEI, fosinopril, both in vivo and in vitro, using 24 h glomeruli cultures. RESULTS: Results showed that a cholesterol-rich diet significantly increased serum cholesterol, proteinuria and glomerular eicosanoid secretion, and caused macrophage-ED1 cell deposits in the glomerular mesangium. Segmentary lesions only appeared in those rats with the highest percentage of glomerular xanthomatous (macrophage-ED1) cells. Ang II, per se, caused a marked rise in glomerular prosaglandin E2 and thromboxane B2. The inhibition of Ang II synthesis with fosinopril reduced all the parameters listed above, whereas Ang II (10(-6)M) increased the secretion of TxB2 and tended to increase PGE2 secretion in glomerular culture. CONCLUSIONS: In conclusion, exogenous cholesterol per se may contribute to nephropathy by increasing eicosanoid secretion, serum lipid profile, urinary protein excretion and the development of glomerular lesions. Fosinopril reduced all these parameters probably by its effects on Ang II. |
| Four cholesterol-sensing proteins Lange, Y. and T. L. Steck (1998), Curr Opin Struct Biol 8(4): 435-9. Abstract: What is the connection among the following three medical conditions: Niemann-Pick type C disease (a cause of mental retardation and early death), systemic lipidosis (in which an obscure side effect of numerous drugs transforms lysosomes into lamellar bodies), and holoprosencephaly (a catastrophe in embryonic development)? Recent evidence suggests that the pathogenesis in each use involves impaired sensing of cellular cholesterol. |
| Four frequently used test systems for serum cholesterol evaluated by isotope dilution gas chromatography-mass spectrometry candidate reference method Thienpont, L. M., K. G. Van Landuyt, et al. (1996), Clin Chem 42(4): 531-5. Abstract: We evaluated the performance of four frequently used cholesterol test systems, using split-sample measurements with a panel of 79 patients' specimens and isotope dilution gas chromatography-mass spectrometry (ID GS-MS) as a comparison method. The test systems were from Beckman, a Boehringer Mannheim, Merck, and Johnson & Johnson Clinical Diagnostics, performed on the Synchron CX7, Hitachi 717, Mega, and Ektachem 250 analyzers, respectively. The liner regression data for the method comparison ID GS-MS as independent variable (x) were for Beckman: slope = 1.012, intercept = 0.0243 mmol/L, dispersion (S(y/x)) = 0.1303 mmol/l, and correlation coefficient (r) = 0.9867; for Boehringer Mannheim: slope = 1.002, intercept = 0.114 mmol/L, Sy/x = 0.0759 mmol/L, r = 0.9954; for Merck: slope = 1.034, intercept = -0.0613 mmol/L, Sy/x = 0.0886 mmol/L, r = 0.9941; and for Johnson & Johnson Clinical Diagnostics: slope = 1.007, intercept = 0.01 mmol/L, Sy/x = 0.15 mmol/L, and r = 0.9811. These data demonstrate excellent state-of-the-art cholesterol measurement for some of the most widely used test systems. |
| Fourier transform infrared spectroscopy of aqueous dispersions of phosphatidylserine-cholesterol mixtures Brumfeld, V., D. Bach, et al. (1991), Eur Biophys J 19(6): 287-93. Abstract: The effect of cholesterol on vibrational spectra in the non polar and in the polar region of dimyristoyl phosphatidylserine (DMPS) and of phosphatidylserine from bovine spinal cord (PS) has been investigated. The small shifts in the methylene CH stretching frequencies after taking into account the contribution of the cholesterol spectrum were interpreted as a combined effect of cholesterol on the conformation of the chains and of the lesser contributions of the cholesterol methyl groups. Cholesterol also influences the ratio of the trans (1465 cm-1) to the lower wavelength (1457 cm-1) CH2 bending bands. No significant direct effect of cholesterol on the vibration of the polar residues was discerned. The small shift of the carboxylate band observed below the phase transition is probably due to the change in the intermolecular zwitterions when the average distance between the neighboring polar groups increases due to incorporation of cholesterol molecules. |
| Fowkes et al's "Serum cholesterol, triglycerides, and aggression in the general population" Bond, A. J. (1993), Br J Psychiatry 163: 666-8. Abstract: "A higher than expected number of violent deaths and suicides in coronary prevention trials has provoked interest in the possibility that low serum cholesterol concentrations are associated in the general population with personality characteristics predisposing to aggressive and suicidal behaviour. We have investigated this possibility in the Edinburgh Artery Study. We measured serum lipid concentrations in blood samples taken from fasting subjects and assessed personality characteristics on the Bedford Foulds Personality Deviance Scales in a random sample of 1,592 men and women aged 55-74 years, selected from age-sex registers of ten general practices in Edinburgh. Serum cholesterol concentration was not significantly associated with aggression in men, but it was associated in multivariate analysis (though not univariate analysis) with denigratory attitudes towards others among women. However, serum triglyceride concentration was related, especially in men, to hostile acts (r = 0.13, P < 0.001) and domineering attitude (r = 0.12, P < 0.001) independently of age, total and HDL cholesterol, cigarette smoking, and alcohol consumption. Subjects taking part in prevention trials have higher triglyceride concentrations than the general population and the relation between serum triglyceride concentration and aggression merits further investigation." |
| FR171456, a novel cholesterol synthesis inhibitor produced by Sporormiella minima No. 15604. I. Taxonomy, fermentation, isolation, physico-chemical properties Hatori, H., T. Shibata, et al. (2004), J Antibiot (Tokyo) 57(4): 253-9. Abstract: FR171456 and FR173945, novel and potent cholesterol synthesis inhibitors, have been isolated from the fermentation broth of a fungal strain No. 15604. This strain was identified Sporormiella minima from its mycological characteristics. FR171456 and FR173945 strongly inhibited cholesterol synthesis in human hepatoma cell line Hep G2. These compounds also have in vitro antifungal activity against Candida albicans and Aspergillus fumigatus. |
| FR171456, a novel cholesterol synthesis inhibitor produced by Sporormiella minima No. 15604. II. Biological activities Hatori, H., T. Shibata, et al. (2004), J Antibiot (Tokyo) 57(4): 260-3. Abstract: Novel cholesterol synthesis inhibitors FR171456 and FR173945 were isolated from the culture broth of Sporormiella minima No. 15604. FR171456 strongly inhibited the cholesterol synthesis and up-regulated the LDL-receptor expression in human hepatoma cell line Hep G2. Single oral administration of FR171456 inhibited in vivo hepatic sterol synthesis in rats. And FR171456 shows a significant serum cholesterol-lowering effect in a cholesterol fed rabbit model. |
| Fractional efflux and net change in cellular cholesterol content mediated by sera from mice expressing both human apolipoprotein AI and human lecithin:cholesterol acyltransferase genes Fournier, N., V. Atger, et al. (1999), Atherosclerosis 147(2): 227-35. Abstract: Human lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of cholesterol and is postulated to participate in the physiological process called reverse cholesterol transport. We have used transgenic mice (Tgm) expressing either both human apolipoprotein AI (apo AI) and human LCAT genes or only the human apo AI gene (HuAILCAT or HuAI Tgm, respectively) to assess the consequences of LCAT overexpression on serum lipid and lipoprotein profiles and on the ability of each serum to promote bidirectional flux of cholesterol between serum and Fu5AH hepatoma cells. Mean serum LCAT activity of HuAILCAT Tgm was 2-fold increased compared to the HuAI group (48+/-9 vs. 24+/-5 nmol/ml per h, P<0.01 for HuAILCAT and HuAI Tgm, respectively) and the cholesterol esterification rates were not significantly different between the two groups of animals (66+/-11 vs. 74+/-18 nmol/ml per h for HuAILCAT and HuAI Tgm, respectively). HuAILCAT Tgm exhibited higher total cholesterol serum values (2.3-fold) due to an increase in both HDL-cholesterol (1. 9-fold) and non-HDL-cholesterol (3-fold). The HDL particles from HuAILCAT Tgm were relatively phospholipid depleted and cholesterol enriched compared to HuAI mice. When cells were incubated for six hours with the mouse serum, the fractional efflux of radiolabeled cholesterol was slightly increased with the HuAILCAT Tgm (1.2-fold) but the increase in intracellular cholesterol content was also 2-fold higher than with the HuAI Tgm. Fu5AH can be viewed as a model for the evaluation of bidirectional flux of cholesterol in SR-BI-rich cells. In this model LCAT overexpression in mice, by increasing both HDL and non-HDL-cholesterol, mostly enhances the uptake of cholesterol by the cells, which would be of benefit for the last step of reverse cholesterol transport in hepatocytes. |
| Fractional esterification rate of cholesterol and ratio of triglycerides to HDL-cholesterol are powerful predictors of positive findings on coronary angiography Frohlich, J. and M. Dobiasova (2003), Clin Chem 49(11): 1873-80. Abstract: BACKGROUND: We examined the predictive value of various clinical and biochemical markers for angiographically defined coronary artery disease (aCAD). Specifically, we assessed the value of the ratio of plasma triglyceride (TGs) to HDL-cholesterol (HDL-C) and the fractional esterification rate of cholesterol in plasma depleted of apolipoprotein B (apoB)-containing lipoproteins (FER(HDL)), a functional marker of HDL and LDL particle size. METHODS: Patients (788 men and 320 women) undergoing coronary angiography were classified into groups with positive aCAD(+) and negative aCAD(-) findings. Patient age, body mass index, waist circumference, blood pressure (BP), medications, drinking, smoking, exercise habits, and plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-unesterified cholesterol, HDL-C, TGs, FER(HDL), apoB, log(TG/HDL-C), and TC/HDL-C were assessed. Lipids and apoproteins were measured by standard laboratory procedures; FER(HDL) was determined by a radioassay. RESULTS: Members of the aCAD(+) group were older and had a higher incidence of smoking and diabetes than those in the aCAD(-) group. The aCAD(+) group also had higher TG, apoB, FER(HDL), and log(TG/HDL-C) and lower HDL-C values. aCAD(+) women had greater waist circumference and higher plasma TC and TC/HDL-C. aCAD(+) men, but not women, had higher plasma LDL-C. In the multivariate logistic model, the significant predictors of the presence of aCAD(+) were FER(HDL), age, smoking, and diabetes. If only laboratory tests were included in the multivariate logistic model, FER(HDL) appeared as the sole predictor of aCAD(+). Log(TG/HDL-C) was an independent predictor when FER(HDL) was omitted from multivariate analysis. CONCLUSIONS: FER(HDL) was the best laboratory predictor of the presence of coronary atherosclerotic lesions. |
| Fractional esterification rate of cholesterol in high density lipoprotein (HDL) can predict the particle size of low density lipoprotein and HDL in patients with coronary heart disease Ohta, T., K. Saku, et al. (1997), Atherosclerosis 135(2): 205-12. Abstract: Fractional esterification rate of cholesterol in high density lipoprotein (HDL) (FERHDL) can predict the size distribution and physicochemical characteristics of HDL in plasma. In the present study, we investigated the correlation of FER(HDL) with the particle size of low density lipoprotein (LDL) (LDL-size) in 111 patients (81 males and 30 females) with coronary heart disease (CHD). The correlations of FER(HDL) and LDL-size with conventional lipid and lipoprotein parameters were also studied. FER(HDL) was closely associated with LDL-size (males: r = -0.618, females: r = -0.629, P < 0.001). Plasma levels of TG, HDL-cholesterol (HDL-C), HDL2-cholesterol (HDL2-C) and apo B were also associated with LDL-size in male CHD patients (r = -0.534, 0.314, 0.358, and -0.482, P < 0.01 or 0.001), while plasma levels of TG and apo B were associated with LDL-size in female patients (r = -0.350 and -0.348, P < 0.05). In a stepwise multiple regression analysis, FER(HDL) alone accounted for 38 and 40% of the variability in LDL-size in male and female CHD patients, respectively. Other parameters accounted for an additional 6-10%. With respect to the relation between FER(HDL) and HDL subfractions, FER(HDL) related only to HDL2-C (males: r = -0.640, females: r = -0.652, P < 0.001). This result suggests that FER(HDL) is better able to predict the presence (or absence) of large HDL, rather than that of small HDL. All these data taken together, suggest that FER(HDL) is a useful tool to predict the particle size of both LDL and HDL, even in CHD patients. |
| Fractional esterification rate of cholesterol in high density lipoprotein is correlated with low density lipoprotein particle size in children Ohta, T., Y. Kakiuti, et al. (1997), J Lipid Res 38(1): 139-46. Abstract: Small low density lipoprotein (LDL) particles are thought to be more atherogenic than larger LDL particles, although this association may depend on plasma triglyceride (TG) and high density lipoprotein (HDL) levels. To help prevent coronary artery disease (CAD), it may be useful to understand risk factors during childhood and adolescence. In the present study, we evaluated low density lipoprotein particle size (LDL-size) by 2-16% gradient gel electrophoresis in 70 healthy children (30 boys and 40 girls) along with conventional lipid and lipoprotein parameters which are thought to affect LDL-size. The fractional and molar esterification rates (FER and MER) of cholesterol in plasma and HDL were also determined. As expected, plasma levels of TG, HDL-cholesterol (HDL-C) and apoA-I were closely associated with LDL-sizes in both sexes (boys: r = -0.694, 0.708 and 0.701, girls: r = -0.579, 0.551 and 0.539, P < 0.001). However, a closer association was found between FER in HDL (FER(HDL)) and LDL-size (boys: r= -0.874, girls: r= -0.642, P < 0.001). In a stepwise multiple regression analysis, FER(HDL) alone accounted for 76% and 41% of the variability in LDL-size in boys and girls, respectively. MER in HDL accounted for additional 4% and 19% in boys and girls, respectively. Other parameters, including plasma TG, HDL-C and apoA-I had no significant additional effects. Thus, the determination of FER(HDL) is useful to predict the particle size of LDL in children. |
| Fractionation of livers following diosgenin treatment to elevate biliary cholesterol Roman, I. D., A. Thewles, et al. (1995), Biochim Biophys Acta 1255(1): 77-81. Abstract: The plant saponin, diosgenin, is known to induce a marked increase in biliary cholesterol/phospholipid ratio. We reasoned that putative biliary lipid supply vesicles might be similarly enriched with cholesterol. Seven-day diosgenin feeding to rats resulted in significantly increased biliary cholesterol and cholesterol/phospholipid ratio, but had no effect on total cholesterol or phospholipid content of the liver. Subcellular fractionation of livers showed no selective increase in any fraction (nuclear, mitochondrial, lysosomal, microsomal) of the homogenate. Further subfractionation of microsomal or nuclear (plasma membrane) fractions also showed no difference between control and diosgenin groups. Thus, no intracellular vesicle fraction has been identified with the provision of the enhanced biliary cholesterol and the results are discussed in terms of the possible involvement of cytosolic lipid-binding proteins as putative lipid carriers to the canalicular membrane as an alternative to the presence of the lipid in lipid supply vesicles. |
| Free and esterified epidermal cholesterol in psoriasis Fortinskaia, E. S., T. I. Torkhovskaia, et al. (1995), Vestn Ross Akad Med Nauk(3): 57-9. Abstract: The levels of epidermal total, free and esterified cholesterol were studied in psoriatic patients. Lipids were isolated from the areas of psoriatic lesions and from the normally appearing epidermis by the authors' non-invasive surface extractive method. The quantity of cholesterol was given in microgram per square centimeter. Fifty six and 11 healthy persons were examined. The skin cholesterol levels were twice-four-fold higher in the patients than in the healthy subjects. The same levels were noted from the areas of lesion and from normally appearing epidermis. The proportion of an esterified fraction decreased mainly in the normally appearing epidermis areas, especially in severe psoriasis. The role of the findings was also discussed. |
| Free and esterified fatty acid and cholesterol synthesis in adult males and its effect on the doubly-labelled water method Haggarty, P., P. Shetty, et al. (2000), Br J Nutr 83(3): 227-34. Abstract: The purpose of the present study was to estimate whole-body fatty acid and cholesterol synthesis in weight-stable adults and to determine the likely effect on the doubly-labelled water (DLW) method for measuring energy expenditure. Synthesis was measured by 2H incorporation over 14 d in six adult males in approximate energy balance following noradrenaline infusion to maximize mobilization of free fatty acid from adipose tissue. The inter-individual variation in synthesis rates was large and in one subject the proportion of free fatty acid synthesized was ten times that of the mean of the rest of the group; the fasting concentration of esterified fatty acid in this subject was five times that of the rest of the group indicating likely violation of the assumptions underlying the calculation of whole-body synthesis. After 14 d of labelling in the other five subjects, 0.9 (SEM 0.3)% of the circulating free fatty acid, 9.3 (SEM 3.0)% of the esterified fatty acid, 14.6 (SEM 2.4)% of the free cholesterol and 28.3 (SEM 3.7)% of esterified cholesterol had been synthesized de novo. A high rate of synthesis correlated with a low pre-dose 2H abundance both within and between lipid classes suggesting that natural 2H abundance variations in some lipid classes may be used to determine their metabolic origin. Whole-body synthetic rates were 8 g/d for fatty acid and 0.3-0.5 g/d for cholesterol. These values correspond to very small errors on DLW-derived estimates of CO2 production; -2.5 litres/d for fatty acid and -0.1 to -0.2 litres/d for cholesterol. These results, obtained in subjects typically consuming a diet with a lower fat and cholesterol content that the typical Western diet, suggest that the DLW method is unlikely to be affected by fatty acid and cholesterol synthesis in subjects in energy balance consuming a typical Western diet. |
| Free cholesterol concentrations in the high-density lipoprotein subfraction-3 as a risk indicator in patients with angiographically documented coronary artery disease Smuts, C. M., H. F. Weich, et al. (1994), Coron Artery Dis 5(4): 331-8. Abstract: BACKGROUND: The pathophysiology of plasma lipoprotein metabolism has long been linked to coronary artery disease (CAD). The present study evaluated the association between plasma lipoprotein lipid and apolipoprotein (apo) components and CAD in a group of 80 consecutive Caucasian patients undergoing coronary angiography. METHODS: Coronary cineangiography was carried out using the Judkins technique and the lesions quantified by calculating a coronary artery lesion score (CALS). Very low- and low-density lipoproteins (VLDL and LDL) were separated by ultracentrifugation, and high-density lipoprotein (HDL) and HDL subfraction-3 (HDL3) isolated by a differential precipitation procedure. Apo A-I, A-II, and B were assayed by endpoint laser nephelometry using specific antibodies. Total cholesterol, free cholesterol, and fatty acid concentrations were measured by gas-liquid chromatography, and lecithin: cholesterol acyltransferase (LCAT) activity by the decrease in the concentration of free cholesterol. RESULTS: On the basis of the presence of CAD, the 80 patients were divided into two groups: 52 (65%) with CAD (mean CALS = 7.8) and 28 (35%) without CAD (zero CALS). The lipoprotein fraction that most clearly differentiated the groups was HDL cholesterol concentration, with a mean +/- SEM value of 36.5 +/- 1.5 mg/dl for those with CAD and 45.1 +/- 2.1 mg/dl for those without (P < 0.01). The mean HDL3 cholesterol concentration was 29.9 +/- 1.2 mg/dl for patients with CAD and 37.4 +/- 1.8 mg/dl for those without (P < 0.001). These differences in HDL cholesterol and HDL3 cholesterol were mainly caused by differences in the free cholesterol component, with a mean HDL free cholesterol level of 10.8 +/- 1.1 and 16.1 +/- 1.4 mg/dl (P < 0.01), and a mean HDL3 free cholesterol level of 7.6 +/- 0.6 and 11.9 +/- 0.8 mg/dl (P < 0.001) in patients with and without CAD, respectively. Plasma LCAT activity was decreased in patients with CAD (P < 0.05), as were the apo A-I and A-II concentrations in both the HDL (P < 0.001) and HDL3 (P < 0.001) fractions. No significant association was found between CAD and HDL2 cholesterol or plasma total cholesterol, LDL cholesterol, or VLDL cholesterol concentrations. A stepwise discriminant analysis revealed that HDL3 free cholesterol was the only variable selected. Using HDL3 free cholesterol as a screening variable for CAD (cutoff 10.55 mg/dl), the sensitivity for CAD was 87% and the specificity for non-CAD 67%. The positive and negative predictive values of HDL3 free cholesterol were 82 and 75%, respectively. CONCLUSION: We have shown that the concentrations of HDL cholesterol and HDL3 most clearly differentiated between patients with and without CAD. |
| Free cholesterol deposition in the cornea of human apolipoprotein A-II transgenic mice with functional lecithin: cholesterol acyltransferase deficiency Julve-Gil, J., E. Ruiz-Perez, et al. (1999), Metabolism 48(4): 415-21. Abstract: We have developed several lines of transgenic animals that overexpress different levels of human apolipoprotein A-II (apoA-II). The 11.1 transgenic line has human apoA-II in plasma at threefold the level in normolipidemic humans and a functional lecithin:cholesterol acyltransferase (LCAT) deficiency. The latter is a biochemical phenotype similar to that of fish-eye disease (FED), which is characterized by free cholesterol (FC) and phospholipid accumulation in the cornea, leading to opacity and impaired vision. To assess whether the metabolic alterations in these mice also lead to lipid accumulation in the cornea, we fed them on a long-term regular chow or high-fat/high-cholesterol (HF/HC) diet. The 11.1 transgenic mice showed a moderate accumulation of FC in the cornea, but only when fed the regular chow diet. This FC accumulation was less severe than the accumulation described in FED, which may explain the lack of corneal opacity in these mice. Electron microscopy and immunoblotting analysis of the cornea of 11.1 transgenic mice in comparison to control mice showed (1) a mild but nevertheless more intense intracytoplasmatic lipid particle deposition in the epithelial cells and (2) a decrease of immunoreactive apoA-I in the area of Bowman's layer and at the superficial stroma. The serum capacity to cause cholesterol efflux from rat fibroblasts was decreased in 11.1 transgenic mice, but only in those fed a regular chow diet. We conclude that 11.1 human apoA-II transgenic mice may be a useful model for studies of early lipid deposition in the cornea and its possible prevention. |
| Free cholesterol enhances adenoviral vector gene transfer and expression in CAR-deficient cells Worgall, S., T. S. Worgall, et al. (2000), Mol Ther 1(1): 39-48. Abstract: Efficient adenovirus vector-mediated gene transfer depends on the presence of sufficient amounts of the high-affinity coxsackie-adenovirus (Ad) receptor (CAR) on the surface of the target cell leading to receptor-mediated endocytosis of the vector. The present study evaluates the effect of free cholesterol, a lipid component of endocytic vesicles, on Ad uptake into CAR-deficient cells. Infection in the presence of free cholesterol at its maximum solubility in water led to increased binding, uptake, and expression of Ad in human skin fibroblasts and alveolar macrophages, two primary human cells known to be deficient in CAR. The effect of free cholesterol was maximal at its solubility maximum in aqueous solution. Increase of Ad vector-mediated gene transfer with cholesterol was dependent on the lack of CAR receptor expression on the surface and was diminished by overexpression of CAR in CAR-deficient cells. Cholesterol-mediated increase of Ad-mediated gene expression was dependent on coincubation of both cholesterol and Ad and was not dependent on the cholesterol content of the cell. Increased Ad vector-mediated gene expression in the presence of free cholesterol was also observed in murine skin in vivo. Structural analysis of the Ad-cholesterol mixture showed complexation between Ad particles leading to formation of multivirus aggregates due to hydrophobic interaction. The addition of free cholesterol with Ad vectors may be a simple way to increase Ad-mediated gene transfer to cells that are poor targets due to their lack of a sufficient number of Ad receptors. |