| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| High density lipoprotein deficiency with xanthomas. A defect in reverse cholesterol transport caused by a point mutation in the apolipoprotein A-I gene Lackner, K. J., H. Dieplinger, et al. (1993), J Clin Invest 92(5): 2262-73. Abstract: A 7-yr-old girl with high density lipoprotein (HDL) deficiency and xanthomas has been identified in a Turkish kindred with repetitive consanguinity. She has severely reduced HDL-cholesterol and no apolipoprotein (apo) A-I. ApoA-II is reduced, whereas apoA-IV and apoC-III are normal. ApoB and low density lipoprotein (LDL)-cholesterol are increased. This is reflected in hypercholesterolemia. VLDL and IDL particles are low, and serum triglycerides are normal. The genetic defect could be identified as a base insertion into the third exon of the apoA-I gene. This leads to a nonsense peptide sequence beginning at amino acid 5 of the mature plasma protein and early termination of translation. The patient is homozygous for this mutation. Pedigree analysis indicated an autosomal dominant inheritance with no evidence of another genetic defect of lipoprotein metabolism in the kindred. In HDL deficiency, HDL binding to leukocytes was increased compared to normal. In the postprandial state, binding of labeled HDL3 to leukocytes is unchanged. This is in contrast to results with postprandially isolated leukocytes from controls or Tangier patients, which have a reduced binding capacity for HDL3. These results indicate that postprandial HDL precursors may compete the binding of labeled HDL3. The metabolic consequences of HDL deficiency were analyzed. There is only a small number of HDL-like particles containing apoA-II, apoA-IV, apoE, and lecithin/cholesteryl acyl transferase. The C-apolipoproteins were normal in the proband. Due to the lack of HDL they can only associate with apoB-containing particles, where they may interfere with cellular uptake. Thus, pure apoA-I deficiency leads to a complex metabolic derangement. |
| High density lipoprotein loses its effect to stimulate efflux of cholesterol from foam cells after oxidative modification Nagano, Y., H. Arai, et al. (1991), Proc Natl Acad Sci U S A 88(15): 6457-61. Abstract: In this study, we performed oxidative modification of high density lipoprotein (HDL) in vitro. The amount of lipid peroxide increased when either HDL2 or HDL3 was incubated with phosphate-buffered saline containing 5 microM CuSO4 for 24 h at 37 degrees C, indicating that both fractions of HDL were oxidatively modified. This modification resulted in denaturation of apolipoprotein AI on SDS/PAGE and increased the negative charge on agarose gel electrophoresis. When incubated with macrophage-derived foam cells, native HDL caused a marked efflux of cholesterol from them, leading to a decrease in the amount of cholesteryl ester in the cells. However, oxidized HDL showed a lessened effect on the decrease of cholesteryl ester in foam cells. These data suggest that oxidative modification of HDL may stimulate development of atherosclerosis by limiting efflux of cholesterol from foam cells. |
| High density lipoprotein metabolism is altered by dietary cholesterol but not fat saturation in guinea pigs Lin, E. C., M. L. Fernandez, et al. (1995), Atherosclerosis 112(2): 161-75. Abstract: To study dietary fat and cholesterol effects on plasma high density lipoprotein (HDL) metabolism and rates of apolipoprotein (apo) A-I catabolism, guinea pigs were fed 15% (wt/wt) lard- or corn oil-based diets with 0.01% (basal), 0.08%, 0.17% or 0.33% cholesterol. Absorbed dietary cholesterol provided 6%, 50%, 100% and 200%, respectively, of the daily endogenous cholesterol synthetic mass. While total plasma cholesterol concentrations increased significantly above basal levels at the 0.17% and 0.33% cholesterol intakes, plasma apo E-free HDL (EoHDL) cholesterol concentrations did not increase significantly until the 0.33% cholesterol level (P < 0.001). Fractional catabolic rates (FCR) of injected 131I-apo A-I were not altered by dietary treatment, either fat saturation or cholesterol, but were inversely correlated with plasma EoHDL cholesterol levels (r = -0.622), suggestive of a regulatory role of turnover rates on HDL cholesterol levels independent of dietary treatment. Analysis of the high affinity EoHDL binding to isolated hepatic membranes suggested that hepatic binding was not a determinant of HDL catabolism, as dietary cholesterol-induced decreases in Bmax (binding capacity) were not correlated with changes in apo A-I FCR. Even though dietary cholesterol was associated with increased plasma EoHDL cholesterol and with decreased HDL binding protein Bmax, these values did not correlate with each other nor with effects on apo A-I FCR. |
| High density lipoprotein phospholipid composition is a major determinant of the bi-directional flux and net movement of cellular free cholesterol mediated by scavenger receptor BI Yancey, P. G., M. de la Llera-Moya, et al. (2000), J Biol Chem 275(47): 36596-604. Abstract: The role of high density lipoprotein (HDL) phospholipid in scavenger receptor BI (SR-BI)-mediated free cholesterol flux was examined by manipulating HDL(3) phosphatidylcholine and sphingomyelin content. Both phosphatidylcholine and sphingomyelin enrichment of HDL enhanced the net efflux of cholesterol from SR-BI-expressing COS-7 cells but by two different mechanisms. Phosphatidylcholine enrichment of HDL increased efflux, whereas sphingomyelin enrichment decreased influx of HDL cholesterol. Although similar trends were observed in control (vector-transfected) COS-7 cells, SR-BI overexpression amplified the effects of phosphatidylcholine and sphingomyelin enrichment of HDL 25- and 2.8-fold, respectively. By using both phosphatidylcholine-enriched and phospholipase A(2)-treated HDL to obtain HDL with a graded phosphatidylcholine content, we showed that SR-BI-mediated cholesterol efflux was highly correlated (r(2) = 0.985) with HDL phosphatidylcholine content. The effects of varying HDL phospholipid composition on SR-BI-mediated free cholesterol flux were not correlated with changes in either the K(d) or B(max) values for high affinity binding to SR-BI. We conclude that SR-BI-mediated free cholesterol flux is highly sensitive to HDL phospholipid composition. Thus, factors that regulate cellular SR-BI expression and the local modification of HDL phospholipid composition will have a large impact on reverse cholesterol transport. |
| High density lipoprotein subpopulations from galactosamine-treated rats and their transformation by lecithin:cholesterol acyltransferase Matsuura, J. E. and J. B. Swaney (1991), J Lipid Res 32(4): 581-94. Abstract: It is known that an acute hepatotoxicity is produced in rats by intraperitoneal administration of galactosamine; a consequence of this treatment is a marked deficiency of lecithin:cholesterol acyltransferase (LCAT) activity in the plasma compartment. In this study high density lipoprotein (HDL) from galactosamine-treated rats was isolated, resolved into subpopulations, and characterized. In contrast to HDL from control rats, which elutes from gel filtration columns as a single peak and has a diameter of 13.1 nm, HDL from the galactosamine-treated animals was found to elute in five major zones with diameters of 7.8-35 nm. Characterization of these subpopulations has revealed that the larger fractions are enriched in apolipoprotein E, phospholipid, and cholesterol, but contain little cholesteryl ester, while the smallest two fractions contain mainly apolipoprotein A-I, are enriched in phospholipid, and have 50-60% of their cholesterol in the ester form. Incubation of HDL from treated rats with a source of LCAT activity plus low and very low density lipoproteins caused transformation of these subpopulations into a species which, by size and composition, was essentially identical to control rat HDL. In addition, when the subpopulations were individually incubated with purified human lecithin:cholesterol acyltransferase and bovine serum albumin, there was a similar convergence toward a moderate particle size approximating control rat HDL. Cross-linking studies showed that incubation with LCAT activity reduced the heterogeneity of the treated rat HDL. We conclude that the galactosamine treatment induces a complex mixture of HDL that bears strong similarities to the small, apoA-I rich and large, apoE-rich particles seen in LCAT deficiency or secreted by hepatic cells in culture. Furthermore, these species appear to coalesce in the presence of the d greater than 1.21 g/ml fraction of control serum to yield a fairly homogeneous population that resembles control rat HDL in size, composition, and apoprotein content. |
| High density lipo-protein-cholesterol Bhatia, R. S. (1992), J Assoc Physicians India 40(7): 492. |
| High density lipoprotein-cholesterol changes in children with high cholesterol levels at birth Bastida, S., F. J. Sanchez-Muniz, et al. (2002), Eur J Pediatr 161(2): 94-8. Abstract: The predictive value of serum lipoprotein concentrations at birth for the same parameters later in life is under debate. A group of 20 children displaying high total cholesterol (TC) levels at birth (group 2) were compared at age 4 years with 18 control children who had presented a normal lipoprotein profile at birth (group 1). There was a significant correlation between TC, low density lipoprotein-cholesterol, high density lipoprotein (HDL)-cholesterol, and apolipoprotein (Apo) A-I levels at age 4 years and at birth. The increases in TC and HDL-cholesterol levels from birth to age 4 years were significantly lower (P < 0.05, P < 0.01, respectively) in group 2 than in the control group and inversely correlated with the concentrations of these parameters at birth. The increases in HDL-cholesterol and Apo A-I levels were higher in males while those of triacylglycerol and Apo B were higher in females (P < 0.05). However, the increases in TC and HDL-cholesterol were higher in controls (P< 0.05). Diets of children of both groups were similar regarding the energy contribution of saturated, monounsaturated and polyunsaturated fatty acids, although children from group 2 ate less fish and omega-3 fatty acids (P < 0.05). CONCLUSION: the present data suggest for the first time that when high density lipoprotein-cholesterol levels are high at birth, those levels increase less during the first four years of life. Moreover, low density lipoprotein-cholesterol increased about five times as much as high density lipoprotein-cholesterol did in controls and about 15 times as much as in the children with high cholesterol at birth. |
| High density lipoprotein-mediated cholesterol uptake and targeting to lipid droplets in intact L-cell fibroblasts. A single- and multiphoton fluorescence approach Frolov, A., A. Petrescu, et al. (2000), J Biol Chem 275(17): 12769-80. Abstract: Fluorescent sterols, dehydroergosterol and NBD-cholesterol, were used to examine high density lipoprotein-mediated cholesterol uptake and intracellular targeting in L-cell fibroblasts. The uptake, but not esterification or targeting to lipid droplets, of these sterols differed >100-fold, suggesting significant differences in uptake pathways. NBD-cholesterol uptake kinetics and lipoprotein specificity reflected high density lipoprotein-mediated sterol uptake via the scavenger receptor B1. Fluorescence energy transfer showed an average intermolecular distance of 26 A between the two fluorescent sterols in L-cells. Indirect immunofluorescence revealed that both fluorescent sterols localized to L-cell lipid droplets, the surface of which contained adipose differentiation-related protein. This lipid droplet-specific protein specifically bound NBD-cholesterol with high affinity (K(d) = 2 nM) at a single site. Thus, NBD-cholesterol and dehydroergosterol were useful fluorescent probes of sterol uptake and intracellular sterol targeting. NBD-cholesterol more selectively probed high density lipoprotein-mediated uptake and rapid intracellular targeting of sterol to lipid droplets. Targeting of sterol to lipid droplets was correlated with the presence of adipose differentiation related protein, a lipid droplet-specific protein shown for the first time to bind unesterified sterol with high affinity. |
| High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport von Eckardstein, A., J. R. Nofer, et al. (2001), Arterioscler Thromb Vasc Biol 21(1): 13-27. Abstract: High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol from cells of the arterial wall to the liver and steroidogenic organs. Enhancement of cholesterol efflux and of reverse cholesterol transport (RCT) is considered an important target for antiatherosclerotic drug therapy. Levels and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. In vitro experiments as well as genetic family and population studies and investigation of transgenic animal models have revealed that HDL cholesterol plasma levels do not necessarily reflect the efficacy and antiatherogenicity of RCT. Instead, the concentration of HDL subclasses, the mobilization of cellular lipids for efflux, and the kinetics of HDL metabolism are important determinants of RCT and the risk of atherosclerosis. |
| High density lipoproteins and reverse cholesterol transport: lessons from mutations von Eckardstein, A. and G. Assmann (1998), Atherosclerosis 137 Suppl: S7-11. Abstract: High density lipoproteins (HDL) encompass structurally and functionally heterogeneous particles. Two-dimensional nondenaturing polyacrylamide gradient gel electrophoresis (2D-PAGGE) and subsequent immunoblotting helps to differentiate quantitatively minor HDL-subclasses from the bulk of HDL, which contains apo A-I and has electrophoretic alpha-mobility. Pulse-chase experiments identified the quantitatively minor HDL subclasses prebeta1-LpA-I, gamma-LpE and LpA-IV as initial and fast acceptors of cell-derived cholesterol and alpha-migrating HDL (i.e. alpha-LpA-I) as a late and slow acceptor. In plasmas of patients with certain forms of familial HDL-deficiency such as apo A-I deficiency and Tangier disease, prebeta1-LpA-I, gamma-LpE and LpA-IV represent the only HDL particles and account for the significant residual cholesterol efflux capacity of these plasmas. These particles, however, also fulfill important roles in reverse cholesterol transport of normal plasma. Prebeta1-LpA-I, for example, is generated, during the interconversion of HDL by lipid transfer proteins. Thus, incubation of plasma with phospholipid transfer protein increases the concentration of prebeta1-LpA-I and in parallel increases the cholesterol efflux capacity of plasma indicating that lipid transfer proteins modulate cholesterol efflux by modification of HDL subclass composition. Apo E and gamma-LpE are of special interest for reverse cholesterol transport since macrophages can produce apo E. |
| High density lipoproteins with differing apolipoproteins: relationships to postprandial lipemia, cholesteryl ester transfer protein, and activities of lipoprotein lipase, hepatic lipase, and lecithin: cholesterol acyltransferase Mowri, H. O., J. R. Patsch, et al. (1994), J Lipid Res 35(2): 291-300. Abstract: To gain insight into metabolic determinants of high density lipoproteins (HDL) containing apolipoproteins A-I and A-II (LpA-I/A-II) and those containing A-I, but devoid of A-II (LpA-I), the plasma concentration of LpA-I and LpA-I/A-II within the HDL2 and HDL3 density spectrum was measured in 14 normolipidemic male subjects on a standardized diet. Apolipoprotein plasma concentrations of HDL subspecies were compared with the magnitude of postprandial lipemia, activities of lipoprotein lipase and hepatic lipase in postheparin plasma, plasma lecithin:cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) mass. Plasma levels of LpA-I/A-II were 2.5 times higher than levels of LpA-I (123 +/- 20 vs. 48.3 +/- 22.1 mg protein/dl) and the partition of LpA-I and LpA-I/A-II between HDL2 and HDL3 differed in that the proportion of LpA-I associated with HDL2 was greater than that of LpA-I/A-II (23 +/- 19 vs. 6 +/- 6%, P < 0.002). With increasing levels of HDL2, the proportion of LpA-I in HDL2 increased (P < 0.002). Furthermore, levels of LpA-I and LpA-I/A-II were strongly correlated within the HDL2 but not within the HDL3 density region. Plasma levels of LpA-I, but not LpA-I/A-II, were inversely correlated with the magnitude of postprandial lipemia. However, activities of lipoprotein lipase and hepatic lipase tended to show stronger associations with the partition of LpA-I/A-II between HDL2 and HDL3 than with that of LpA-I. Within the HDL3, but not the HDL2 density spectrum, LpA-I/A-II exhibited a positive association with plasma LCAT activity, while LpA-I displayed an inverse association with plasma CETP mass. These results are consistent with differences in substrate properties of LpA-I and LpA-I/A-II for lipoprotein modifying enzymes and imply different, but overlapping metabolic pathways of LpA-I and LpA-I/A-II. |
| High density lipoproteins, reverse transport of cholesterol, and coronary artery disease. Insights from mutations Assmann, G., A. von Eckardstein, et al. (1993), Circulation 87(4 Suppl): III28-34. Abstract: BACKGROUND. The reverse cholesterol transport model is most widely used to explain both the role of high density lipoproteins (HDL) in lipid metabolism and the inverse association between HDL cholesterol plasma concentration and the risk for coronary artery disease (CAD). As familial HDL cholesterol deficiency is frequently paralleled with a family history of premature CAD, much interest has been directed toward the molecular defects in apolipoproteins and lipid-transfer enzymes involved in the formation and metabolism of HDL. Knowledge of the basic defects in rare HDL-deficiency syndromes and apolipoprotein variants provides genetic markers of whether the presence of these molecular defects accounts for low HDL cholesterol levels and the accompanying coronary risk. METHODS AND RESULTS. Sequence analysis of proteins or DNA from patients with HDL deficiency or hyperalphalipoproteinemia as well as from randomly screened probands has helped to identify a series of molecular defects in the genes of apolipoprotein (apo) A-I, apo A-II, apo A-IV, apo C-III, lecithin cholesterol acyltransferase, and cholesterol ester-transfer protein. Some of these mutations were associated with absent and low levels of HDL cholesterol in homozygous and heterozygous carries, respectively, but only a few homozygotes were at an increased risk of CAD. These mutations were invaluable for gaining insight into structural-functional relations in HDL metabolism. CONCLUSIONS. Mutations in the genes of apo A-I, apo A-II, apo A-IV, apo C-III, lecithin cholesterol acyltransferase, and cholesterol ester-transfer protein can influence HDL cholesterol plasma concentrations but do not account for the coronary risk associated with low HDL cholesterol levels. In general, these observations suggest that the low HDL concentrations in CAD patients are not a reflection of impaired reverse cholesterol transport but rather of some other metabolic disturbances, such as catabolism of triglyceride-rich particles. |
| High dietary intake of phytosterol esters decreases carotenoids and increases plasma plant sterol levels with no additional cholesterol lowering Clifton, P. M., M. Noakes, et al. (2004), J Lipid Res 45(8): 1493-9. Abstract: The objective of this study was to measure the effects on serum lipids and plasma phytosterols of 6.6 g/day phytosterols from three foods (bread, breakfast cereal, and spread) consumed for 12 weeks compared with a diet that was not enriched with phytosterols. Thirty-five subjects undertook a nonrandomized, single-blind study consisting of a 2 week baseline period, 6 weeks on high-phytosterol intake, 6 weeks on high-phytosterol intake plus increased fruit and vegetable intake, and a final 2 week washout period. Serum total cholesterol decreased by 8.3% from 6.59 to 6.04 mmol/l, and LDL cholesterol decreased by 12.6% from 4.44 to 3.88 mmol/l. Plasma phytosterol levels increased by 45% (sitosterol) and 105% (campesterol). Cholesterol-adjusted plasma alpha- and beta-carotene levels decreased by 19-23%, lutein by 14%, and lycopene by 11%. Levels of alpha-carotene and lutein increased with extra fruit and vegetables. Only lycopene failed to increase during the washout phase. There were no significant changes in biochemical parameters. Serum LDL cholesterol lowering with 6.6 g/day ingested phytosterols was in the range seen with 1.6-3.2 g/day phytosterols. Lowering of plasma carotenoids was greater than that seen with lower phytosterol intake and was partially reversed by increased fruit and vegetable intake. |
| High dietary iron concentrations enhance the formation of cholesterol oxidation products in the liver of adult rats fed salmon oil with minimal effects on antioxidant status Brandsch, C., R. Ringseis, et al. (2002), J Nutr 132(8): 2263-9. Abstract: The aim of this study was to investigate the effect of high dietary iron concentrations on the antioxidant status of rats fed two different types of fat. Four groups of male adult Sprague-Dawley rats were fed diets with adequate (50 mg iron supplemented per kg diet) or high (500 mg iron supplemented per kg diet) iron concentrations with either lard or salmon oil as dietary fat at 100 g/kg for 12 wk. The antioxidant status of the rats was profoundly influenced by the type of fat. Rats fed salmon oil diets had higher concentrations of thiobarbituric acid-reactive substances (TBARS) (P < 0.001), various cholesterol oxidation products (COP) (P < 0.001), total and oxidized glutathione (P < 0.05) and a lower concentration of alpha-tocopherol (P < 0.05) in liver and plasma than rats fed lard diets. The iron concentration of the diet did not influence the concentrations of TBARS, the activities of superoxide dismutase and glutathione peroxidase or the concentration of alpha-tocopherol in plasma or liver. The activity of catalase (P < 0.01) and the concentrations of total, oxidized and reduced glutathione (P < 0.05) in liver were slightly but significantly higher in rats fed high iron diets than in rats fed adequate iron diets, irrespective of the dietary fat. Rats fed the high iron diets with salmon oil, moreover, had higher concentrations of various COP in the liver (P < 0.001) than rats fed adequate iron diets with salmon oil. These results suggest that feeding a high iron diet does not generally affect the antioxidant status of rats but enhances the formation of COP, particularly if the diet is rich in polyunsaturated fatty acids. |
| High dietary methionine plus cholesterol exacerbates atherosclerosis formation in the left main coronary artery of rabbits Zulli, A., D. L. Hare, et al. (2004), Atherosclerosis 176(1): 83-9. Abstract: Although mild hyperhomocysteinemia is a risk factor for cardiovascular events and mortality, there is no evidence to suggest that mild hyperhomocysteinemia stimulates coronary artery atherosclerosis formation. OBJECTIVE: To compare the development of coronary artery atherosclerosis in rabbits following the induction of hyperhomocysteinemia and hypercholesterolemia through diet, and whether the combination of these risk factors exacerbated atherosclerosis formation. METHODS: New Zealand White rabbits were fed for 12 weeks either a control diet, a 1% methionine diet (Meth), a 0.5% cholesterol diet (Chol) or the combination of the two diets (MethChol). Using volumetric stereological techniques, we quantitated the volume of intima, media and lumen of the left main coronary artery (LMCA). RESULTS: Atherosclerosis was present in the Chol group, and increased in the MethChol group. There was no atherosclerosis in the control or Meth groups. CONCLUSIONS: These results underscore the difference in the atherogenicity of hypercholesterolemia alone and mild hyperhomocysteinemia alone. Thus, we suggest that isolated mild hyperhomocysteinemia is not a risk factor for the initiation of coronary artery atherosclerosis formation over a short period of time, but may act in conjunction with other risk factors to further increase plaque formation. |
| High dose of fluvastatin sodium (XU62-320), a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, lowers plasma cholesterol levels in homozygous Watanabe-heritable hyperlipidemic rabbits Kurokawa, J., K. Hayashi, et al. (1995), Biochim Biophys Acta 1259(1): 99-104. Abstract: The effects of fluvastatin sodium (XU62-320), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on plasma cholesterol and triacylglycerol levels were investigated using homozygous Watanabe-heritable hyperlipidemic (WHHL) rabbit, an LDL-receptor-deficient animal which expresses a hepatic LDL receptor activity less than 5% that of control rabbits. Plasma levels of total, VLDL- and LDL-cholesterol were decreased profoundly after oral administration of fluvastatin at a dose of 50 mg/kg per day for 4 weeks. Plasma triacylglycerol levels were not affected by fluvastatin. Hepatic HMG-CoA reductase activity increased by 3-fold and hepatic LDL receptor activity increased by only 3.7-fold, as calculated by Scatchard plot analysis, with fluvastatin administration for 4 weeks, and the hepatic mRNA level for the rabbit LDL receptor was increased by 3-fold. Combined administration of fluvastatin (50 mg/kg per day) and cholestyramine, a bile acid sequestrant resin, at a level of 2% of the diet for 4 weeks more profoundly decreased plasma total, VLDL- and LDL-cholesterol levels with induction of hepatic cholesterol 7 alpha-hydroxylase and no further induction of the hepatic LDL receptor. Plasma triacylglycerol levels were increased by the combination treatment. These results suggest that high dose of fluvastatin sodium is effective in lowering plasma cholesterol levels in homozygous WHHL rabbits through the shared mechanisms involving decrease in production and secretion of cholesterol from the liver and the induction of hepatic LDL receptor. Additional effect of cholestyramine on decrease in plasma cholesterol levels seems to be due to the further decrease in hepatic cholesterol secretion by up-regulation of hepatic cholesterol 7 alpha-hydroxylase. |
| High doses of simvastatin, pravastatin, and cholesterol reduce brain cholesterol synthesis in guinea pigs Lutjohann, D., M. Stroick, et al. (2004), Steroids 69(6): 431-8. Abstract: Recent epidemiological studies suggest that inhibitors of 3-hydroxy-3-methyl-glutaryl CoA reductase, so-called statins, are effective in lowering the prevalence of Alzheimer's disease. Whether the effect of statins is due to a local inhibition of cholesterol synthesis in the brain or whether it is mediated by the reduced levels of cholesterol in the circulation is not known. In the present work, we tested the possibility that high doses of lipophilic and hydrophilic statins, simvastatin and pravastatin, respectively, or a diet high in cholesterol could affect cholesterol homeostasis in the brain of guinea pigs. The total brain cholesterol levels were not affected by high-dose simvastatin or pravastatin treatment. Significantly lower levels of the cholesterol precursor lathosterol and its ratio to cholesterol were found in the brains of simvastatin and pravastatin-treated animals. 24S-Hydroxycholesterol, the transportable form of cholesterol across the blood-brain barrier, was significantly lower in the brain of pravastatin-treated animals. Excessive cholesterol feeding resulted in higher serum cholesterol levels but did not affect total brain cholesterol level. However, de novo cholesterol synthesis in the brain seemed to be down-regulated, as indicated by lower absolute levels and cholesterol-related ratios of lathosterol compared with controls. The passage of deuterium-labeled cholesterol across the blood-brain barrier in one animal was found to be approximately 1%. Our results suggest that brain cholesterol synthesis in guinea pigs can be slightly, but significantly, influenced by high doses of lipophilic and hydrophilic statins as well as by high dietary cholesterol intake, while total brain cholesterol content and thus, cholesterol homeostasis is maintained. |
| High fat, high cholesterol diets alter low density lipoprotein size and binding affinity in monkeys Hannah, J. S., K. Yamane, et al. (1997), Atherosclerosis 132(1): 19-27. Abstract: The purpose of this study was to examine the effects of various dietary fats on low density lipoprotein (LDL) binding in an in vitro system where receptor number is not regulated. Cynomolgus monkeys were fed diets containing 37% of energy from fat, with various degrees of saturation, and 0.4 mg/kcal cholesterol or low-fat (13% of energy), low cholesterol (0.03 mg/kcal) chow. Plasma LDL was isolated after 16 weeks. The fatty acid composition of LDL showed enrichment corresponding to the dietary fats consumed, and the high fat, high cholesterol diets produced marked hypercholesterolemia compared to chow feeding. Of those fed the high fat diets, monkeys fed the fish oil diet had the highest LDL cholesterol concentrations, 13.25 +/- 0.77 mmol/l, while those fed the safflower oil diet had the lowest, 7.51 +/- 3.31. LDL from chow fed monkeys had the lowest binding affinity; the Kd was 26.2 +/- 8.7 microg/ml, nearly twice that of the high fat diets (P = 0.003). No significant differences in binding were found between the different high fat diets, although there was a trend toward lower affinity in the diets enriched in polyunsaturated fat. LDL size was affected by diet with chow fed monkeys having the smallest average LDL, 259.3 +/- 1.7 A compared to the other groups (P = 0.03). Monkeys fed the fish oil diet tended to have smaller LDL, but this was not significantly different from the other high fat diets. Binding affinity was correlated with LDL size, r = 0.54, P < 0.01. LDL composition, as measured by apo B/cholesterol ratio, was altered by feeding a high fat, high cholesterol diet. The ratio was reduced in the LDL samples from monkeys fed the high fat diets compared to those fed chow, but this ratio was not significantly correlated with binding. Thus, it appears that increasing dietary fat and cholesterol intake increases LDL size and binding affinity, such that LDL metabolism may be altered independently from effects on receptor number; the type of dietary fat does not seem to influence this process when fat and cholesterol content is very high. |
| High glucose levels do not directly impair cellular binding of HDL3 or HDL-mediated efflux of cholesterol from human skin fibroblasts Duell, P. B. and E. L. Bierman (1991), Acta Diabetol 28(2): 174-8. Abstract: The excess risk of atherosclerosis that is associated with diabetes mellitus cannot be completely accounted for by other known risk factors. Recent studies have suggested that increased glycation of high density lipoproteins (HDL) at high glucose concentrations causes functional abnormalities that might contribute to accelerated atherosclerosis. Other investigators also have shown that elevated glucose concentrations can stimulate the activity of protein kinase C in cultured cells. Because protein kinase C appears to be involved in HDL receptor-mediated efflux, the hypothesis that a high glucose concentration in vitro might modulate HDL-mediated efflux of cholesterol from human fibroblasts was tested. These studies indicate that a high glucose level alone does not affect the interaction of normal HDL3 with cultured human skin fibroblasts. |
| High intake of cholesterol results in less atherogenic low-density lipoprotein particles in men and women independent of response classification Herron, K. L., I. E. Lofgren, et al. (2004), Metabolism 53(6): 823-30. Abstract: The influence of a high-cholesterol diet on the atherogenicity of the low-density lipoprotein (LDL) particle was examined by measuring LDL peak diameter and composition, LDL susceptibility to oxidation, and the distribution of cholesterol between LDL subclasses. The crossover intervention randomly assigned 27 premenopausal women and 25 men (18 to 50 years) to an egg (640 mg/d additional dietary cholesterol) or placebo (0 mg/d additional dietary cholesterol) diet for 30 days, followed by a 3-week washout period. Subjects were classified as either hyperresponders (>2.5 mg/dL increase in plasma cholesterol for each 100 mg additional dietary cholesterol consumed) or hyporesponders to dietary cholesterol. Sex was found to have a significant effect on 3 of the parameters examined. LDL peak diameter was significantly larger (P <.005) in females (26.78 +/- 0.59 nm, n = 27) as compared with males (26.52 +/- 0.49 nm, n = 25), regardless of response to dietary cholesterol. The LDL particles of the male participants also had a higher number of triglyceride (TG) and cholesteryl ester (CE) molecules (P <.01); however, cholesterol ester transfer protein (CETP) activity was higher in females (P <.05). Response classification also revealed significant differences in the determination of LDL subclasses. Independent of sex, the LDL-1 particle (P <.05), which is considered to be less atherogenic, was predominant in hyperresponders and this finding was associated with increased cholesterol intake (interactive effect, P <.001). In addition, CETP and lecithin: cholesterol acyltransferase (LCAT) activities were higher in hyperresponders during the egg period (interactive effect, P <.05). Sex, response to cholesterol intake, and diet were not found to affect the susceptibility of LDL to oxidation (P > 0.5). Because LDL peak diameter was not decreased and the larger LDL-1 subclass was greater in hyperresponders following egg intake, these data indicate that the consumption of a high-cholesterol diet does not negatively influence the atherogenicity of the LDL particle. |