| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Ability of non-high-density lipoprotein cholesterol and calculated intermediate-density lipoprotein to identify nontraditional lipoprotein subclass risk factors in dialysis patients Belani, S. S., A. C. Goldberg, et al. (2004), Am J Kidney Dis 43(2): 320-9. Abstract: BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) and calculated intermediate-density lipoprotein cholesterol (IDL-C) have been proposed as surrogate markers to estimate apolipoprotein B-containing lipoproteins. The purpose of this study was to determine the validity of non-HDL-C and calculated IDL-C to predict nontraditional lipoprotein risk factors among dialysis patients and to compare the prevalence of these nontraditional risk factors between dialysis modalities. METHODS: The authors performed a cross-sectional analysis comparing standard lipid profile with lipoprotein analysis via nuclear magnetic resonance (NMR) spectroscopy among 186 hemodialysis (HD) and peritoneal dialysis (PD) patients on modern lipid-lowering therapy. RESULTS: The PD group had a significantly higher low-density lipoprotein (LDL) particle concentration (P < 0.005), higher large very low-density lipoprotein (VLDL; P < 0.001), greater small dense LDL (P < 0.001), and lower protective large HDL (P < 0.005). Forty-six (40%) of 118 subjects with LDL-C below goal had at least 1 nontraditional risk factor by NMR spectroscopy. The sensitivity of non-HDL-C method together with triglyceride (TG) value greater than 200 mg/dL (>2.26 mmol/L) to predict nontraditional risk was 13% and increased to 20% if TG values were excluded. A negative correlation was observed between LDL particle size and HDL-C (r2 = 0.269; P < 0.001); the sensitivity of HDL-C to predict LDL size was 92%. There was no relationship between measured IDL by NMR and calculated IDL-C (r2 = 0.005; P = 0.69). CONCLUSION: Non-HDL-C greater than 130 mg/dL (3.4 mmol/L) independent of TG values and HDL-C lower than 40 mg/dL (1.0 mmol/L) may predict nontraditional lipoprotein risk factors among dialysis patients. This is especially applicable to patients on PD, a modality associated with a more atherogenic lipoprotein profile. |
| Abnormal capacity to induce cholesterol efflux and a new LpA-I pre-beta particle in type 2 diabetic patients Brites, F. D., E. Cavallero, et al. (1999), Clin Chim Acta 279(1-2): 1-14. Abstract: In this study, we first characterized the lipoprotein components of serum samples obtained from a group of well-controlled diabetic patients and from healthy subjects in fasting and postprandial states. We then explored some aspects of reverse cholesterol transport in the same population. Patients showed high levels of fasting triglycerides, postprandial triglyceride responses and LpC-III levels (3.18+/-0.86 vs 2.17+/-0.54 mg/dl, P < 0.001). There were also positive correlations between LpC-III and fasting triglycerides (r = 0.82, P < 0.001), total triglyceride area (r = 0.75, P < 0.001) and incremental triglyceride area (r = 0.54, P < 0.001). HDL-C and apo A-I were significantly decreased in diabetic patients due to a selective reduction in LpA-I subfraction, whose antiatherogenic role is generally accepted (37.4+/-8.0 vs 49.2+/-12.5 mg/dl, P < 0.001). In addition, HDL from patients proved to be triglyceride enriched and cholesteryl ester depleted, alterations which were further amplified in the postprandial state. The molar ratio HDL-C/apo A-I + apo A-II, already defined as a predictor of apo A-I fractional catabolic rate, was significantly diminished in the patient group (15.1+/-2.2 vs 20.8+/-3.3, P < 0.001), thus suggesting an accelerated catabolism of apo A-I. For the first time, we describe here the presence of a small apo A-I-containing particle, isolated by two-dimensional electrophoresis and characterized by immunoblotting, only in samples from diabetic patients. This particle that we named pre-beta0, has an apparent molecular weight of 40 kDa. As regards the capacity of serum samples to promote cholesterol efflux from 3Hcholesterol-labeled Fu5AH rat hepatoma cells, patient samples were found to induce significantly lower cholesterol efflux than controls only in the postprandial state (21.2+/-3.3 vs 23.8+/-1.8%, P = 0.012). The presence of pre-beta0 in samples from diabetic patients might therefore be associated to an altered capacity of these serum samples to promote cellular cholesterol efflux. Overall, these abnormalities may contribute to a delay in the reverse cholesterol transport pathway in type 2 diabetic patients. |
| Abnormal cholesterol biosynthesis as in Smith-Lemli-Opitz syndrome disrupts normal skeletal development in the rat Kolf-Clauw, M., F. Chevy, et al. (1998), J Lab Clin Med 131(3): 222-7. Abstract: Smith-Lemli-Opitz syndrome (SLOS) in human infants is a common autosomal recessive malformation syndrome (estimated incidence, 1:20,000). It is characterized clinically by congenital anomalies, especially craniofacial and limb defects, and biochemically by a defect in 7-dehydrocholesterol-delta7-reductase activity (7DHC-reductase), the final enzyme in cholesterol biosynthesis. In previous studies, early administration of the 7DHC-reductase inhibitor AY9944 to pregnant rats resulted in a high frequency of holoprosencephaly, relevant to craniofacial anomalies of SLOS. In order to test the effect of AY9944 on limb development, we treated dams on gestation day 7 (GD7), which delays the biochemical defect to about GD13 to GD14. Sera were sampled on GD12, GD14, and GD21 and cholesterol and dehydrocholesterols (7DHC and 8DHC) were measured by gas-chromatography-mass spectrometry (GC-MS), as for the diagnosis of SLOS. GD21 fetuses were examined for gross malformations and skeletal development. In treated dams, the SLOS biochemical marker 7DHC accounted for one fourth and one third of total sterols, respectively, on GD12 and GD14, and cholesterolemia on these two gestation days was reduced by 50% and 43%, respectively, as compared with control values. This maternal metabolic defect was associated with decrease in fetal weight and delayed ossification. In addition, scapular malformations were observed in four fetuses from three litters. The malformations could have been caused by the same mechanism as holoprosencephaly after early treatment with AY9944. These cholesterol-deficiency-based malformations could have a common cause in the abnormal expression of Hedgehog or other developmental gene proteins, and may thus explain various congenital polymalformative syndromes in humans, including SLOS. |
| Abnormal cholesterol biosynthesis in sitosterolaemia and the Smith-Lemli-Opitz syndrome Salen, G., S. Shefer, et al. (1996), J Inherit Metab Dis 19(4): 391-400. Abstract: We investigated the enzyme defects in two inherited disorders of cholesterol biosynthesis: sitosterolaemia and the Smith-Lemli-Opitz syndrome. In sitosterolaemic homozygotes, plasma plant sterols (sitosterol and campesterol) concentrations are elevated because of enhanced intestinal absorption and diminished removal. Underlying these changes is very low cholesterol biosynthesis to provide extra sterol for cell growth. Extremely reduced activities of HMG-CoA reductase, the rate-controlling enzyme for cholesterol biosynthesis, caused by deficient HMG-CoA reductase mRNA is responsible and is the suspected inherited abnormality. The Smith-Lemli-Opitz syndrome is caused by a block in the last reaction in the cholesterol biosynthetic pathway, the conversion of 7-dehydrocholesterol to cholesterol, which is catalysed by 7-dehydrocholesterol delta 7-reductase. As a result, low plasma and tissue cholesterol with high 7-dehydrocholesterol levels are found in homozygotes, who show characteristic phenotypes of mental retardation, facial dysmorphism, and organ and limb congenital anomalies. Similar biochemical findings are produced in rats fed BM 15,766, an inhibitor of 7-dehydrocholesterol delta 7-reductase. Interestingly, feeding cholesterol can suppress abnormal cholesterol biosynthesis and improve symptoms in homozygotes and rats fed BM 15,766. |
| Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz and the lethal acrodysgenital syndromes Cormier-Daire, V., C. Wolf, et al. (1996), Eur J Pediatr 155(8): 656-9. Abstract: The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterized by dysmorphic facial features with abnormal limbs and genitalia. Two forms have been recognized based on clinical course and severity: the classical SLO (type I) and the lethal acrodysgenital syndrome (type II). Type I SLO has been recently ascribed to a defect in cholesterol synthesis. Taking advantage of a series of seven patients including five type I and two type II SLO, we describe micrognathia, severe microcephaly, major ante and post natal growth retardation and feeding difficulties as consistent features in the disease. In addition, we give support to the presence of abnormal cholesterol levels in the lethal acrodysgenital syndrome but find no correlation between plasma sterol levels and the clinical severity of the disease. CONCLUSION: The identification of the same biochemical defect in both types of Smith-Lemli-Opitz Syndrome suggests that despite major discrepancies in clinical course and severity, type I and type II SLo are probably allelic disorders. |
| Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome Salen, G., G. S. Tint, et al. (1995), Ital J Gastroenterol 27(9): 506-8. Abstract: We measured plasma sterol concentrations in 7 homozygotes with the Smith-Lemli-Opitz syndrome, 5 heterozygotes and rats treated with BM 15.766, the competitive inhibitor of 7-dehydrocholesterol 7-reductase. Low cholesterol associated with markedly elevated 7-dehydrocholesterol concentrations were detected in the plasma of all homozygotes and inhibitor-treated rats. Heterozygotes were clinically normal and, like control subjects, showed only trace amounts of 7-dehydrocholesterol in plasma. We conclude that the Smith-Lemli-Opitz syndrome is due to an inherited defect in 7 dehydrocholesterol 7-reductase which causes the accumulation of 7-dehydrocholesterol and a deficiency of cholesterol in the plasma, a biochemical abnormality that can be reproduced in rats treated with BM 15.766. |
| Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome Salen, G., S. Shefer, et al. (1996), J Lipid Res 37(6): 1169-80. Abstract: The Smith-Lemli-Opitz syndrome is caused by an inherited defect in 7-dehydrocholesterol-delta7-reductase, the enzyme that catalyzes the last reaction in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol. As a result, deficient cholesterol is produced and the precursor 7-dehydrocholesterol and derivatives (8-dehydrocholesterol and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol) accumulate. Tissues (especially brain) deprived of cholesterol, or because of the deposited sterol precursors and derivatives, develop abnormally and function poorly. Replacement with dietary cholesterol may help correct the biochemical defects and improve symptoms. |
| Abnormal cholesterol biosynthesis produced by AY 9944 in the rat leads to skeletal deformities similar to the Smith-Lemli-Opitz syndrome Batta, A. K. and G. Salen (1998), J Lab Clin Med 131(3): 192-3. |
| Abnormal cholesterol distribution among lipoprotein fractions in normolipidemic patients with mild NIDDM Abate, N., G. L. Vega, et al. (1995), Atherosclerosis 118(1): 111-22. Abstract: This study was carried out to identify and define lipoprotein abnormalities in patients with noninsulin-dependent diabetes mellitus (NIDDM) who do not have clinical elevations of cholesterol or triglycerides. Thirty-four male patients with mild NIDDM and normolipidemia (plasma cholesterol < or = 240 mg/dl and triglycerides < or = 250 mg/dl) were compared with 35 healthy male normolipidemic subjects. The two groups had similar age and body mass index. Measurements in the two groups included concentrations and chemical composition of lipoproteins and sizing of low-density lipoprotein (LDL) particles. The patients with NIDDM, compared to control subjects, had two distinct lipoprotein abnormalities: first a significantly reduced level of high-density lipoprotein (HDL) cholesterol (mean +/- S.D., 35 +/- 8 mg/dl vs. 41 +/-10 mg/dl, respectively; P = 0.006), and second, a high cholesterol-to-apolipoprotein (apo) B ratio both in a very low density lipoprotein (VLDL) + intermediate density lipoprotein (IDL) fraction (mean +/- S.D.; 3.2 +/- 0.8 vs. 2.8 +/- 0.9, respectively; P = 0.02) and in LDL fraction (mean +/- S.D.; 1.61 +/- 0.11 vs. 1.52 +/- 0.13, respectively; P = 0.003). Increased cholesterol content in LDL was mainly due to free cholesterol. No differences were detected between the two groups in the frequency of LDL pattern A (major LDL peak > 255 A) and pattern B (major LDL peak < or = 255 A). However, a higher frequency of LDL pattern B was found in NIDDM patients with low plasma total triglyceride concentrations (< 150 mg/dl) compared to the to the control subjects (45% vs. 7%, P = 0.02). Thus in normolipidemic patients with mild NIDDM, the major lipoprotein abnormalities were a low level of HDL cholesterol and compositional changes in LDL and VLDL + IDL fractions. Compositional abnormalities included enrichment of apo B-containing lipoproteins with cholesterol. These lipoprotein abnormalities could have atherogenic potential in patients with mild NIDDM and normolipidemia. |
| Abnormal cholesterol metabolism in imipramine-treated fibroblast cultures. Similarities with Niemann-Pick type C disease Rodriguez-Lafrasse, C., R. Rousson, et al. (1990), Biochim Biophys Acta 1043(2): 123-8. Abstract: Addition of low-density lipoprotein (LDL) to cholesterol-deprived human skin fibroblast cultures treated by imipramine at a 20 microM concentration induced a significant intracellular accumulation of unesterified cholesterol. Intracytoplasmic inclusions were already visible by histochemical filipin staining after 2 h of LDL uptake and were progressively mobilized towards the perinuclear region within 24 h. At this concentration of the drug, the rate of proteolytic 125I-LDL hydrolysis was similar in treated and untreated cells. Treated cells maintained in lipoprotein-deficient medium showed no abnormality, indicating the exogenous origin of the accumulated sterol. Further, the drug induced a drastic dose-dependent impairment of LDL-stimulated cholesterol esterification, not related to an inhibition of acyl CoA:cholesterol acyltransferase, and a significant delay in down-regulation of de novo cholesterol synthesis. However, imipramine did not affect 25-hydroxycholesterol-mediated regulation of the two latter processes. These results resemble those observed in Niemann-Pick type C disease and suggest an impaired mobilization of LDL-derived cholesterol in imipramine-treated cells. |
| Abnormal cholesterol metabolism in Smith-Lemli-Opitz syndrome Elias, E. R. and M. Irons (1995), Curr Opin Pediatr 7(6): 710-4. Abstract: Smith-Lemli-Opitz syndrome (SLOS) is a common autosomal recessive disorder. Children with SLOS present with specific facial dysmorphism and have multiple congenital anomalies including cleft palate, congenital heart disease, genitourinary anomalies, and limb abnormalities. They also manifest severe failure to thrive and mental retardation. A metabolic defect at the final step in the cholesterol biosynthetic pathway has been described in SLOS patients. This defect results in markedly reduced cholesterol levels and abnormal accumulation of cholesterol precursors, particularly 7-dehydrocholesterol. This newly described metabolic defect in humans is one of only a few metabolic errors known to cause multiple birth defects. The biochemical profile of reduced plasma cholesterol levels in association with markedly elevated levels of the cholesterol precursor 7-dehydrocholesterol is now used to confirm the diagnosis of SLOS, which was formerly made on purely clinical grounds. This biochemical abnormality has been confirmed in dozens of patients with SLOS in both the United States and Europe. The severe cholesterol deficiency seen in these patients has multiple effects on health and early childhood development, because cholesterol is an essential component of many cell functions, which explains many of the clinical findings seen in SLOS. |
| Abnormal cholesterol metabolism in the Smith-Lemli-Opitz syndrome: report of clinical and biochemical findings in four patients and treatment in one patient Irons, M., E. R. Elias, et al. (1994), Am J Med Genet 50(4): 347-52. Abstract: We report on four patients with the Smith-Lemli-Opitz (SLO) syndrome who appear to have a defect in cholesterol biosynthesis. The initial results of therapy of one of the patients with cholesterol and bile acids to correct her metabolic abnormalities are described. This finding provides a biochemical marker to help in the diagnosis of this syndrome, may provide insight into the pathogenesis of this disorder, and have therapeutic and prenatal diagnostic implications as well. |
| Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer's disease patients and its relationship to acetyl CoA content Corrigan, F. M., D. F. Horrobin, et al. (1998), Int J Biochem Cell Biol 30(2): 197-207. Abstract: The long-chain fatty acid composition of cholesterol esters, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) from parahippocampal cortex of Alzheimer's disease (AD) patients and control subjects was examined. In general the PC fraction contained less polyunsaturated long-chain fatty acids than did PE, PS or PI. Of the n-6 polyunsaturated long-chain fatty acids, PI contained the greatest incorporation of these acids followed by PE. There were significant differences between controls and AD patients in total n-6 EFAs. Arachidonic acid (C20:4n-6) was the predominant fatty acid of this family found to be present. In AD, PE and PS showed a deficit of adrenic acid (C22:4n-6) content and PE also contained less arachidonic acid. In AD subjects, the cholesterol esters contained significantly less n-3 polyunsaturated fatty acids with, specifically, a reduction in alpha-linolenic acid. Acetyl CoA content of hippocampal cortex was greater in AD patients than in control subjects indicating either an increased extent of oxidative metabolism or a failure to utilise acetyl CoA for anabolic processes. Abnormal magnitude of oxidative processes could give rise to the biosynthesis of PE and PS species containing less n-6 polyunsaturated fatty acids than occurs in control subjects. |
| Abnormal regulation of low density lipoprotein-sensitive events in a cholesterol transport mutant Dahl, N. K., W. G. Gutheil, et al. (1993), J Biol Chem 268(23): 16979-86. Abstract: We have isolated and characterized Chinese hamster ovary cell mutants defective in the intracellular transport of low density lipoprotein (LDL)-derived cholesterol (Dahl, N. K., Reed, K. L., Daunais, M. A., Faust, J. R., and Liscum, L. (1992) J. Biol. Chem. 267, 4889-4896). Mutant 2-2, which exhibits a cholesterol transport defect indistinguishable from the Niemann-Pick C phenotype, shows impaired but not absent LDL-mediated suppression of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity. In parental cells, LDL suppression of HMG-CoA reductase is modulated by two mechanisms, decreased gene transcription and accelerated protein turnover. Using the chimeric protein HMGal as a reporter protein for LDL-mediated turnover and Northern blot analysis to monitor HMG-CoA reductase mRNA levels, we have dissected the contributions of these two regulatory responses to LDL-mediated suppression of HMG-CoA reductase activity. Kinetic modeling using the kinlsq program showed the following. Mutant 2-2 exhibits normal LDL-mediated acceleration of HMGal degradation, coupled with relatively abnormal regulation of mRNA. This suggests that the LDL-cholesterol signaling pathway to the nucleus is defective relative to the signal that results in HMG-CoA reductase turnover. In addition, LDL-mediated acceleration of HMGal turnover occurs well before LDL stimulation of cholesterol esterification in mutant 2-2, whereas these events occur synchronously in the parental cell line. This suggests that more than one pathway or mechanism exists for LDL-cholesterol signaling to the endoplasmic reticulum. |
| Abnormal reverse cholesterol transport in controlled type II diabetic patients. Studies on fasting and postprandial LpA-I particles Cavallero, E., F. Brites, et al. (1995), Arterioscler Thromb Vasc Biol 15(12): 2130-5. Abstract: The high incidence and prevalence of coronary heart disease in diabetes mellitus is clearly established. The usual lipid pattern found in type II diabetic patients is a moderate increase in fasting triglyceride levels associated with low HDL cholesterol levels. These abnormalities are further amplified in the postprandial state. To study the effect of these alterations on reverse cholesterol transport, we isolated lipoprotein containing apoA-I but not apoA-II (LpA-I) particles by immunoaffinity chromatography from the plasma of well-controlled type II diabetic patients and nondiabetic matched control subjects. Different parameters involved in this antiatherogenic pathway were measured in both fasting and postprandial states. Diabetic patients had reduced levels of LpA-I particles that were protein enriched and phospholipid depleted. Gradient gel electrophoresis showed that control LpA-I particles had five distinct populations, whereas diabetic particles lacked the largest one. LpA-I isolated from diabetic plasma exhibited a decreased capacity to induce cholesterol efflux from Ob 1771 adipose cells both in fasting (15.1 +/- 10.0% versus 7.5 +/- 2.7%, P <.05) and postprandial (17.7 +/- 11.2% versus 7.7 +/- 3.9%, P <.05) states, whereas only control particles showed significantly higher ability to promote cholesterol efflux after the test meal (P =.02). Lecithin:cholesterol acyltransferase activity measured with an exogenous substrate showed a 54% increase and an 18% decrease postprandially for control subjects and patients, respectively. Thus, the different abnormalities found in the fasting state were further amplified in the postprandial situation. This resulted in LpA-I particles with aberrant size and composition and decreased ability to accomplish their antiatherogenic role in type II diabetic patients. |
| Abnormalities in cholesterol metabolism cause peripheral neuropathy and dementia in AIDS--a hypothesis Falkenbach, A., S. Klauke, et al. (1990), Med Hypotheses 33(1): 57-61. Abstract: The AIDS dementia complex and peripheral neuropathy in AIDS are considered to be direct or indirect manifestations of HIV infection, yet the pathogenesis in unclear. There are parallels between AIDS and Tangier disease clinically and histopathologically and in lipid metabolism. The neurological disorders in AIDS may be caused by dysfunction of cellular cholesterol transport. Substitution of high density lipoprotein is recommended in the treatment of severe polyneuropathy and dementia in AIDS. |
| Abnormalities in gallbladder function in cholesterol gallstone disease: bile and blood, mucosa and muscle--the list lengthens Shaffer, E. A. (1992), Gastroenterology 102(5): 1808-12. |
| Abnormalities of cholesterol metabolism in diabetes Tomkin, G. H. and D. Owens (1991), Proc Nutr Soc 50(3): 583-9. |
| Abrupt modifications of phospholipid bilayer properties at critical cholesterol concentrations Parasassi, T., A. M. Giusti, et al. (1995), Biophys J 68(5): 1895-902. Abstract: The fluorescence generalized polarization (GP) of 2-dimethylamino-6-lauroylnaphthalene (Laurdan) reveals different effects of cholesterol on the phase behavior of phospholipid bilayers. Phospholipid vesicles composed of gel, liquid-crystalline, and coexisting domains of the two phases have been studied at temperatures from 1 to 65 degrees C, without cholesterol and with cholesterol concentrations of 3-50 mol %. Laurdan GP measurements show the general effect of cholesterol of increasing the molecular dynamics of the gel and of decreasing the molecular dynamics of the liquid-crystalline phase. In the liquid-crystalline phase, the increased order yields Laurdan GP values close to those obtained in the gel phase. At cholesterol concentrations > 15 mol % a phase transition cannot be detected. Using the wavelength dependence of the excitation and emission GP spectra we determine that differences between the two phospholipid phases cannot be detected. In particular, in vesicles composed of coexisting gel and liquid-crystalline phases the GP wavelength dependence characteristic of coexisting domains cannot be observed at cholesterol concentrations > or = 15 mol %. Cholesterol causes the decrease in both the polarity and the dipolar relaxation effects on the neighborhood of the fluorescent naphthalene moiety of Laurdan. Probably because of a cholesterol-induced increase in the bilayer packing, these effects do not occur continuously with the increase of cholesterol concentration in the bilayer. Cholesterol concentrations inducing higher Laurdan GP values have been determined at about 5, 10, 15, 30, and 45 mol % with respect to phospholipids. We propose that the formation of ordered molecular microdomains at critical cholesterol concentrations can explain the occurrence of the observed discontinuities. |
| Absence of ABCA1 mutations in individuals with low serum HDL-cholesterol Woll, P. S., N. Q. Hanson, et al. (2003), Clin Chem 49(3): 521-2. |