摘要:

A glutamine/histldine polymorphism at residue 360 in apolipoprotein (apo) A-IV that generates two electrophoretically detectable isoforms, apo A-IV-1 and apo A-IV-2, affects the plasma concentration of lipoprotein(a) (Lp[a]) in a healthy population. To verify this unexpected association we analyzed the effect of the apo A-IV polymorphism on Lp(a) serum concentrations in 275 male coronary heart disease patients. Allele frequencies of apo A-IV-1 and apo A-IV-2 were 0.917 and 0.083, respectively. In addition, apo A-IV-1/2 heterozygotes showed a 30% lower geometric mean concentration of Lp(a) than apo A-IV-1/1 homozygotes in this study. The relative frequency of Lp(a) concentrations >20 mg/dl was significantly increased by a factor of 2.25 in apo A-IV-1/1 homozygotes. Other lipid parameters were not significantly affected by this apo A-IV polymorphism. Because of the relations between Lp(a) and the fibrinolytlc system, we also analyzed the effect of the apo A-IV polymorphism on hemostatic variables. Apo A-IV-1/2 heterozygosity was associated with a 70% higher geometric mean plasma concentration of D-dimer, i.e., proteolytic fragments of cross-linked fibrin. Plasma concentrations of prothrombin fragments F1+F2, fibrinogen, plasminogen, and plasminogen activator inhibitor-1 were unaffected. In conclusion, our results indicate a hitherto unappreciated role of the apo A-IV gene or a closely linked locus for the regulation of Lp(a) metabolism and hemostasis and also possibly for atherosclerosis and thrombosis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Human cholesterogenesis is measurable as the rate of Incorporation of deuterium derived from deuterium oxide (D2O) within the body water pool into plasma or erythrocyte cholesterol pools. Oral D2O equilibrates across body water, thus enabling extracellular sampling of pools (such as urine) to serve as accurate indicators of intracellular deuterium enrichments at the point of synthesis. Required doses of D2O fall below the threshold associated with negative side effects. Deuterium/carbon incorporation ratios into cholesterol during biosynthesis have been established that are applicable in humans. Models using unconstrained and constrained curve fitting permit improved flexibility in interpretation of deuteriumuptake kinetics. However, sample-size restrictions presently limit the ability of the technique to examine the kinetics within individual lipoprotein species. Correction of enrichment data for proton exchange during the combustion and reduction phases of sample preparation is an additional important procedural concern. In summary, the deuterated-water procedure is a useful tool in studies of human cholesterol synthesis that offers the advantages of short measurement interval, relative noninvasiveness, and provision of a direct index of synthesis in comparison with other available techniques.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

To study the effects of dietary and social manipulations on lesion progression in male monkeys with established atherosclerosis, 83 animals fed a diet containing 1 mg cholesterol per kcal for 14 months were either necropsied (baseline group, n=21) or assigned to one of three experimental conditions: 1) a diet containing a high amount of fat and cholesterol and a stressful social situation (HiFC-stress, n=18); 2) a diet lower in fat and cholesterol and a stressful social situation (LoFC-stress, n=21); or 3) the low-fat, low-cholesterol diet and a nonstressful social situation (LoFC-no stress,n=23).After 28 months, all animals were necropsied. Coronary atherogenesis was arrested among monkeys in the LoFC-stress and LoFC-no stress conditions compared with that of animals in the baseline condition (plaque areas of 0.35 mm2, 0.30 mm1, and 0.38 mm1, respectively). Lesions in animals fed the LoFC diet (both stress and no-stress groups) were significantly smaller than those in monkeys in the HiFC-stress condition (0.96 mm1). Furthermore, aortic cholesterol content was significantly decreased and luminal areas were relatively larger among monkeys in both LoFC conditions compared with animals in the baseline and HiFC-stress conditions (p<0.05 for all). The results demonstrate that a low-fat, low-cholesterol diet can halt plaque development, reduce arterial cholesterol content, and permit compensatory arterial enlargement, processes that were unaffected by social stress in this investigation.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

This report explores the hypothesis that massive cholesteryl ester (CE) accumulation in macrophages, such as that occurring in atheroma foam cells, results in changes in the expression or modification of specific cellular proteins. Two-dimensional (2-D) gel electrophoretic patterns of metabolically labeled cellular proteins from mouse peritoneal macrophages that were loaded with CE (through incubation with acetylated low density lipoprotein [acetyl-LDL] for 4 days) were compared with those of control macrophages. Densitometric analysis of 2-D gel autoradiograms from the cell lysates revealed statistically significant changes in seven cellular proteins (five decreases and two increases). The changes in protein expression (foam cell versus control) ranged from a 458±164% (p<0.001) increase to a 35±34% (p<0.001) decrease(n=U).Incubation of macrophages with /3-very low density lipoprotein, which also increased the CE content of macrophages (albeit to a lesser extent than acetyl-LDL), resulted in changes in five of the seven proteins. In contrast, incubation of cells with LDL, fucoidan, or latex beads, none of which caused CE accumulation, did not lead to significant changes in four of these five proteins. One of these four proteins, which increased fourfold to fivefold in foam cells (Afr=49,00O; isoelectric point of 6.8), was purified by preparative 2-D gel electrophoresis. Internal amino acid sequence of cyanogen bromide fragments of this protein as well as Western blot analysis identified this protein as an isoform of er-enolase. The increased expression of this or-enolase isoform, which was seen as early as day 2 of acetyl-LDL incubation of the macrophages, was diminished by including an inhibitor of cholesterol esterification during the acetyl-LDL incubation period. In conclusion, macrophage foam cell formation is associated with distinct changes in protein expression, including a marked increase in an isoform of a-enolase, suggesting a specific biological adaptation to CE loading.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Rat serosal mast cells contain cytoplasmic secretory granules composed of a proteoglycan matrix in which histamine and neutral proteases are embedded. On stimulation, these granules are exocytosed, but some of them remain in the degranulation channels where on exposure to the extracellular fluid, they lose their histamine and a fraction of their proteoglycans. In vitro, such granule remnants efficiently bind low density lipoprotein (LDL) present in the incubation medium. After a lag period of about 10 minutes, the granule remnants, still within the channels and coated with LDL particles, are internalized by the parent mast cells. During subsequent recovery from degranulation, the apolipoprotein B of the intracellularly located remnant-bound LDL becomes efficiently (up to 70%) degraded by the proteolytic enzymes of the granule remnants. Since the granule remnants lack cholesteryl esterase activity, no LDL cholesterol is made available for cellular nutrition. Instead, selective proteolytic degradation of the bound LDL leads to formation of LDL particles enlarged by fusion on the granule remnant surface. In response to restimulation of the mast cells, about 50% of the fused LDL particles are exocytosed with the granule remnants. Of these, about one in five are expelled into the incubation medium. The granule remnants that again remain in the degranulation channels bind and internalize more LDL. This "round trip" of LDL in mast cells exposed to repeated stimulation constitutes a hitherto-unknown intracellular pathway for modification of LDL.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effect of gemfibrozil on postprandial lipoprotein metabolism was investigated in a 12-week, randomized, double-blind, placebo-controlled trial in 20 non-insulin-dependent diabetic patients with moderate hypertrigryceridemia. The patients were given a meal containing 78 g of fat and 345,000 units of vitamin A to label chylomicrons and their remnants. Plasma obtained at various times during the fat-load test was separated into six fractions by gradient-density ultracentrifugation. Gemfibrozil reduced the postprandial triglyceride response, measured as the area under the time-dependent concentration curve, on average by 32% in whole plasma, by 38% in the Svedberg flotation unit (Sf) 1,100-3,200 chylomicron fraction, by 36% in S, 400-1,100 chylomicrons, and by 38% in the S, 60-400 lipoproteins. Retinyl palmitate, a measure of intestinally derived particles, was reduced in plasma by 34%, in Sr1,100-3,200 by 46%, in S, 400-1,100 by 44%, and in S, 60-400 by 37%. All these reductions were significant in comparison with the placebo group. Particles with Sr<60 were not significantly affected. In contrast to earlier observations in healthy subjects, no significant negative correlations existed between postprandial lipemia and high density lipoprotein cholesterol or the postheparin lipoprotein lipase activity. The reduction of the potentially atherogenic chylomicron remnants may decrease the risk of atherosclerosis in non-insulin-dependent diabetes mellitus, a hypothesis that awaits testing in prospective studies.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The effects of growth hormone treatment of adults with adult-onset pituitary insufficiency on lipoproteins and apolipoproteins were investigated. Nine patients, one women and eight men (age range, 34-58 years), who had been treated for pituitary tumors were studied. They had complete pituitary insufficiency with a duration of at least 1 year. All patients received replacement therapy with thyroid hormones, glucocorticoids, and gonadal steroids. The study had a double-blind, placebo-controlled, crossover design for active treatment with recombinant human growth hormone (0.25-0.5 units/kg per week s.c given each evening) for 6 months. Fasting serum levels of cholesterol; triglycerides; high density lipoprotein and low density lipoprotein cholesterol; apolipoproteins A-I, B, and E; and lipoprotein (a) were measured before and after 6 and 26 weeks of treatment Lipoprotein (a) concentrations increased markedly during treatment and were about twice as high compared with pretreatment levels. Serum cholesterol and low density lipoprotein cholesterol concentrations were decreased after 6 weeks of treatment, but levels had returned to pretreatment levels after 26 weeks. High density lipoprotein cholesterol concentrations increased during treatment and were significantly higher than pretreatment levels after 26 weeks of treatment Serum trigiyceride concentrations did not change significantly, but in two patients with marked hypertriglyceridemia, growth hormone treatment resulted in a marked decrease. Serum concentrations of apolipoproteins A-I, B, and E did not change significantly, but changes in apolipoprotein A-I and B concentrations were in parallel to those observed for high density lipoprotein cholesterol and low density lipoprotein cholesterol, respectively. These results suggest that growth hormone is a major regulator of lipoprotein metabolism and also demonstrate that lipoprotein (a) concentrations are regulated by growth hormone.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The purpose of this study was to characterize the lipoprotein profile in the KKA7mouse, a rodent model of type II diabetes, before and after treatment with the insulin-sensitizing drug pioglitazone. Analysis of the plasma from untreated KKA7mice showed that they were severely hyperglycemic, severely hypertriglyceridemic, and moderately hypercholesterolemic. Agarose column chromatographic analysis showed that essentially all of the triglyceride eluted with very low density lipoprotein, and the majority of the cholesterol eluted with high density lipoprotein. Thus, both the very low density lipoprotein and high density lipoprotein levels were markedly elevated in KKA7mice. Analysis of the lipoproteins by agarose electrophoresis-immunoblotting showed that apoprotein A-I and apoprotein B had aberrant electrophoretic behavior, typical of apoproteins that have been modified by nonenzymatic glycosylation. Treatment of KKA7mice with pioglitazone for 8 days caused a marked reduction in blood glucose and plasma triglyceride concentrations but had no significant effect on plasma cholesterol concentration or distribution. The aberrant electrophoretic behavior of the apoproteins was corrected to normal by drug treatment These data show that the KKA7mouse has a severe dyslipoproteinemia that is probably secondary to its insulin resistance, but that its lipoprotein profile differs significantly from that of the insulin-resistant human in that the majority of the plasma cholesterol is carried in high density lipoprotein, and those high density lipoprotein levels are very high.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The purpose of this study was to determine the relation between vessel wall shear stress and the rate of atherosclerosis progression. Quantitative angiography was used to calculate the change in coronary arterial diameter over 3.0 years in patients enrolled in the Harvard Atherosclerosis Reversibility Project pilot study (n=20 arterial segments). Vessel wall shear stress was calculated by means of a validated finite-difference model of the Navler-Stokes' equation that assumes a coronary flow rate of 8 ml/sec The correlation between vessel wall shear stress and the change in arterial diameter at multiple points (mean, 70) along the length of the artery was then calculated for each of the 20 segments with a focal stenosis. In 15 of the 20 arterial segments there was a significant correlation (p<0.05) between low shear stress and an increased rate of atherosclerosis progression. A Fisher's z transformation was then used to combine the correlation coefficients from all 20 segments. Low shear stress was significantly correlated (z=0.37 ± 0.00074,p< 0.0001) with an increased rate of atherosclerosis progression. This serial quantitative evaluation of human coronary arteries is consistent with previous data that have suggested that low shear stress promotes atherosclerosis progression. Variations in local vessel wall shear stress may explain the previously reported near-independent rate of atherosclerosis progression in multiple lesions within the same patient despite exposure to the same circulating lipoprotein values and systemic hemodynamics.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Patients with familial dysbetalipoproteinemia (FD) associated with the apo E2/2 phenotype exhibit a marked interindividual variability in serum cholesterol and triglyceride concentrations. It has been proposed that this variability is due to a combination of the apo E2/2 phenotype and additional genetic factors implicated in diseases like familial hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypertrigryceridemia. To further explore the nature of this variability, the lipoprotein profiles of 17 patients with FD associated with the apo E2/2 phenotype were analyzed by a density-gradient ultracentrifugation technique and by 2-16% polyacrylamide gel electrophoresis. It was found that all patients with FD were characterized by 1) markedly increased cholesterol concentrations of large very low density lipoprotein (VLDL) (VLDL,) (2.98±3.08 versus 0.08±0.03 mmol/L), small VLDL (VLDLj) (4.68±1.93 versus 0.27±0.13 mmol/L), and intermediate density lipoprotein (DDL) (2.25±0.72 versus 0J9±0.16 mmol/L); 2) decreased low density lipoprotein (LDL) cholesterol level (1.84±0.54 versus 3.36±0.53 mmol/L); and 3) altered composition (enrichment by cholesteryl ester) of VLDL, and VLDL2compared with normolipidemic control subjects. The cholesterol levels of DDL and LDL showed minor interindividual variabilities and were not correlated with serum cholesterol and triglyceride levels. The compositions of VLDL, and VLDL] were independent of the concentrations of lipids in serum. However, the cholesterol concentrations of VLDL, and VLDL2showed considerable interindividual variabilities and were positively correlated with the serum cholesterol concentration (r=0.84 and r=0.95, respectively, bothp<0.001). It is concluded that the marked interindividual variability in the serum cholesterol and triglyceride concentrations in patients with FD is mainly due to variations in the concentrations of VLDL, and VLDL2. This suggests that a combination of the apo E2/2 phenotype and genetic abnormalities in the metabolism of triglyceride-rich lipoproteins may be required for the expression of FD.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID