Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute changes in low density lipoprotein cholesterol levels may be due to both a change in the number of LDL particles/ml of plasma and an alteration in the amount of cholesterol per LDL particle. Since LDL cholesterol levels are known to alter abruptly after myocardial infarction, the composition of LDL was determined in nine patients who suffered an uncomplicated transmural myocardial infarction. In six of these, LDL cholesterol levels fell whereas in three LDL cholesterol rose during the first nine days in hospital. The contents of B protein, free cholesterol, phospholipid, cholesterol ester and triglyceride in LDL were determined in the initial sample and the subsequent sample showing the greatest changes in LDL cholesterol level. The proportion of the LDL molecule contributed by B protein, free cholesterol and phospholipid did not differ significantly between the two samples. In contrast, when LDL cholesterol fell, the decrease in the proportion of cholesterol ester was disproportionately greater than in triglyceride. The opposite was observed when LDL cholesterol rose. This inverse relation between changes in LDL cholesterol ester and triglyceride could be expressed by Y = -1.02 X -0.17 (r = -0.94). These data are consistent with a pseudomicellar model of LDL in which the surface components are present in fixed amounts but the interior shell of cholesterol ester and triglyceride varies in an inverse relation depending on the absolute LDL concentration.
Atherosclerosis 1977 Jul
PMID:Predictable changes in low density lipoprotein composition after acute myocardial infarction. 19 78

The structural and compositional changes occurring during in vitro chemical modification of apolipoprotein B-100 (apo B), the apolipoprotein component of low density lipoproteins (LDL), were investigated in this study. The functional properties of chemically modified apo B and especially its potential to induce accumulation of cholesterol esters in macrophages were related to the structural changes of apo B. Acetylation, maleylation or malondialdehyde conjugation did not significantly affect the lipid composition of LDL. However, the unsaturated cholesteryl esters content, especially that of cholesteryl arachidonate was significantly decreased through Cu-oxidation. The number of reactive lysine residues in apo B was decreased by Cu-catalyzed LDL oxidation, acetylation, maleylation and by malondialdehyde conjugation. The number of free cysteines decreased from six in native apo B-100 to three in Cu-oxidized LDL. The tryptophan fluorescence intensity decreased most in malondialdehyde-conjugated LDL and in Cu-oxidized LDL, compared with acetylated and maleylated LDL. The secondary structure of native and chemically modified LDL was measured by attenuated total reflection infrared spectroscopy and by circular dichroism. No significant changes were observed in the secondary structure of any of the modified LDL. These data suggest that neither acetylation, malondialdehyde treatment or even Cu-oxidation substantially altered the secondary structure of apo B, in spite of significant modifications in the primary structure. Incubation of chemically modified LDL with J774 macrophages induced an accumulation of cellular cholesteryl esters and foam cell formation. The highest cholesterol accumulation was induced after malondialdehyde treatment of LDL. These data suggest that the cellular uptake and accumulation of modified LDL is not modulated by changes in the apo B structure. Rather it seems dependent upon the net charge of the apo B protein and probably involves the modification of critical lysine residues.
Atherosclerosis 1992 Dec
PMID:Structural and functional properties of apolipoprotein B in chemically modified low density lipoproteins. 146 63

To test the hypothesis whether low density lipoprotein (LDL) poor in cholesteryl ester from patients with coronary artery disease (CAD) express reduced capacity to regulate cellular sterol and lipoprotein metabolism, we compared the abilities of CAD-LDL and control-LDL to suppress receptor-mediated LDL degradation; activate acyl-CoA: cholesterol acyltransferase (ACAT); and regulate sterol synthesis rates in HL-60 promyelocytic leukemic cells. The ratio of apolipoprotein B to cholesteryl ester was 23% higher for CAD-LDL than control-LDL (P less than 0.01), whereby CAD-LDL contained less cholesterol per particle than control-LDL and would be predicted to exert a reduced regulatory effect on sterol and lipoprotein metabolism than control-LDL at the same level of apo B protein. The results indicate that receptor-mediated 125I-LDL degradation rates were 43% higher for cells pre-incubated with CAD-LDL than with control-LDL (P less than 0.04), consistent with CAD-LDL having a lower ability to down-regulate LDL (apo B/E) receptor expression. When LDL degradation rates were expressed as a percentage of the rate of HL-60 cells incubated in lipoprotein-free medium, the mean LDL degradation rate for cells pre-incubated with CAD-LDL was 56% of untreated cells, while for cells incubated with control-LDL the average value was 41%. The data indicate that the suppression of receptor-mediated LDL degradation was proportional to the LDL cholesterol concentration in the medium. ACAT activity was 42% lower in cells pre-incubated with CAD-LDL as compared to control-LDL (P = 0.002), suggesting that the entry of cholesterol into the ACAT substrate pool was lower in cells pre-incubated with CAD-LDL. There was no significant difference in the rate of sterol synthesis from [14C]acetate between cells pre-incubated with CAD-LDL versus control-LDL. The data support the hypothesis that LDL from CAD patients exhibit a decreased ability to down-regulate apo B/E receptor activity which could in part account for the previously observed increase in LDL degradation by mononuclear leukocytes from CAD patients (Shi et al., Atherosclerosis, 85 (1990) 127).
Atherosclerosis 1991 Dec
PMID:Reduced regulatory capacity of low density lipoproteins from patients with coronary artery disease. 166 63

The 3' end of the apo B gene is highly polymorphic. Two point mutations in the coding sequence of the gene create EcoRI (E+, E-) and XbaI (X+, X-) RFLPs. The two loci are in random association and the frequency of the four haplotypes, E+X+, E+X-, E-X+ and E-X- in the normolipidaemic population are 0.68, 0.30, 0.02 and 0.00, respectively. Although the polymorphic nucleotide underlying the EcoRI RFLP creates an amino acid substitution in the apo B protein (Glu----Lys) in a region close to a putative LDL-receptor recognition site(s), we find no statistically significant difference in the frequency of the apo BGlu and apo BLys alleles in hyperlipidaemic patients (familial hypercholesterolaemia, type IIA with no tendon xanthomas, IIB and probably IV) and the normolipidaemic population. In contrast, we confirm previous findings, that the X+ allele is in linkage disequilibrium with a genetic locus that predisposes to the development of higher fasting plasma triglyceride levels than the X- allele. We have characterized a highly polymorphic region immediately 3' to the apo B gene. At least 5 alleles of this locus exist in the population and our family studies show it should be an extremely informative locus to use in studies where polymorphic or mutant apo B alleles are suspected to underly certain forms of familial hyperlipidaemia. DNA sequence analysis of this highly polymorphic locus shows that the variation is entirely attributable to the number of times the simple repeating sequence 5'-TTTATAATTAAAATATTTATAATTAAATAT-3' is present.
Atherosclerosis 1988 Jan
PMID:Characterization of genetic markers in the 3' end of the apo B gene and their use in family and population studies. 289 57

In a random sample of 22 normolipidaemic male Caucasian individuals, 35-49 years old, homozygosity for the X2 allele (cutting site) of the XbaI RFLP of the apo B gene was associated with higher mean total cholesterol and LDL-cholesterol concentration. These individuals also had significantly lower LDL fractional catabolic rate (P less than 0.03) and a lower degradation of LDL by mononuclear cells in vitro. We propose that the XbaI polymorphism is associated with amino acid changes in the apo B protein which influences LDL binding to the LDL-receptor. This modulates catabolism of this lipoprotein and so contributes to variability of plasma cholesterol levels.
Atherosclerosis 1988 May
PMID:The fractional catabolic rate of low density lipoprotein in normal individuals is influenced by variation in the apolipoprotein B gene: a preliminary study. 289 60

Low density lipoprotein (LDL) receptor deficiency, which causes homozygous familial hypercholesterolemia (FH), is accompanied by a gross disturbance in the metabolism of apolipoprotein (apo) B-containing lipoproteins. Not only is plasma LDL increased, but also the less dense lipoproteins (of very low and intermediate density) accumulate to a similar extent. Only the largest triglyceride-rich subfraction of very low density lipoprotein (VLDL) is not affected. The metabolic disturbance is characterized by oversynthesis of apo B and a defect in its clearance along the length of the delipidation cascade from VLDL to LDL. This phenomenon leads to delayed transit of particles through the system, extending the residence time of the B protein in the plasma by three- to fourfold. Receptor deficiency, therefore, results in accumulation of a number of lipoprotein species that have been implicated in the pathogenesis of atherosclerosis.
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PMID:Lipoprotein metabolism in familial hypercholesterolemia. 291 31

We previously reported the finding of phytosterolemia, xanthomatosis, and hyperapobetalipoproteinemia (hyperapoB) in five siblings in a large Amish pedigree ascertained through a 13-year-old boy who died suddenly from advanced coronary atherosclerosis. Here, we present further analyses of the plasma levels of the plant sterol, sitosterol, of low density (beta) lipoprotein (LDL) sterol, and of LDL B protein. Of 254 relatives and spouses of the proband, 90.5% were examined. A series of genetic models were explored using a pedigree analysis where parameters reflecting frequency, transmission, and penetrance of putative genotypes were examined simultaneously using a maximum likelihood approach. Segregation analysis of the sitosterol levels showed that the phenotype of sitosterolemia was controlled by a rare autosomal recessive gene. There was also significant familial correlation in plasma sitosterol levels that was attributed to a polygenic component under a mixed model but could also be due to shared environments such as diets. The recessive model was supported by our finding that the plasma sitosterol levels in the parents and in six children born to three of the five sitosterolemics were less than 1 mg/dl, well within the normal range. The phenotype of hyperapoB is based on an elevated level of LDL B protein in the presence of a normal LDL cholesterol level (low LDL sterol to LDL B ratio). For both LDL sterol and LDL B, a polygenic model showed a slightly greater improvement in ln likelihood than did the Mendelian single locus model when both were compared to a sporadic model. Similar results were obtained for sterol levels of high density (alpha) lipoprotein (HDL) sterol. When segregation analysis was performed using the ratio of LDL sterol to LDL B, the Mendelian single locus model gave a slightly better fit to the data than did the polygenic model. While the analyses presented here provided unequivocal evidence for the recessive phenotype of phytosterolemia, we also identified a possible single gene factor that could account for the major portion of the strong familial aggregation in the ratio of LDL sterol to LDL B, and to a lesser extent LDL B. However, there is clear evidence of familial aggregation for these traits in this pedigree beyond that due to Mendelian components.
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PMID:Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia. 370

The death of a 13-year-old boy from coronary atherosclerosis prompted the study of an Amish family. Five of his twelve sibs had tendon and tuberous xanthomas, and increased plasma plant sterols, particularly beta-sitosterol. The plasma level of the major apoprotein of low density lipoprotein (LDL), the B protein, was very high (mean 173 mg/dl) in these five sibs, while the LDL cholesterol level was moderately increased (209 mg/dl). Four other sibs and both parents had an increased LDL B protein level with a normal or mildly raised plasma total and LDL cholesterol level (hyperapobeta-lipoproteinaemia). Evidence for coronary artery disease was found in both parents and three xanthomatous sibs. The original family with beta-sitosterolaemia and xanthomatosis, described in 1974, was re-examined. The proband and her sister had persistent phytosterolaemia and normocholesterolaemia but increased LDL B protein levels. Both parents, two uncles, and three of four grandparents had increased LDL B protein levels and normal total and LDL cholesterol levels. The proband's father had atypical angina pectoris. People with the full syndrome (phytosterolaemia, xanthomas, and hyperapobetalipoproteinaemia) are most probably homozygous for a mutant allele. An increased LDL B protein level permits the identification of heterozygotes in these families, even though in the fasting state they show no phytosterolaemia. The homozygote and probably the heterozygote are at increased risk for cardiovascular atherosclerotic disease.
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PMID:Hyperapobetalipoproteinaemia in two families with xanthomas and phytosterolaemia. 611 91

Researchers disagree on whether plasma triglyceride levels are an independent risk factor for atherosclerotic coronary artery disease. We hypothesized that patients with endogenous hypertriglyceridemia would differ: Some would have normal values of plasma low-density lipoprotein (LDL) B protein; others, despite their normal level of LDL cholesterol, would have increased levels of LDL B protein. We believe the latter patients--those with hyperapobetalipoproteinemia--would be the ones at risk for atherosclerosis. We studied two populations. Group 1, consisting of 162 patients with type IV lipoprotein patterns, was divided into two groups. One subgroup (A), which included 38 patients with elevated plasma LDL B atherosclerotic disease than the other subgroup (B) of 36 patients with normal levels of plasma LDL B protein (10 patients versus two, p less than 0.02). Group 2 consisted of 100 patients who had had myocardial infarction. Eighty-one percent of the 47 hypertriglyceridemic and 70% of the 53 normotriglyceridemic patients had elevated plasma LDL B protein levels (129 mg/dL or greater)--a proportion significantly higher than that in Group 1 (p less than 0.001). Thus, an elevated plasma level of LDL B protein not only identifies subgroups of patients with type IV lipoprotein patterns, but also may be an important marker for atherosclerotic disease.
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PMID:Association of hyperapobetalipoproteinemia with endogenous hypertriglyceridemia and atherosclerosis. 714 91

The possible mechanisms of action of probucol on the metabolism of low density lipoprotein and of high density lipoprotein were studied in 5 hyperlipidaemic subjects. The kinetics of LDL-B protein and of HDL-AI protein were determined by 2-pool analysis of specific radioactivity-time curves after reinjection of 131I-labelled LDL and 125I-labelled HDL at the end of placebo and treatment periods. Probucol increased the fractional removal rate of LDL in 4, an action probably linked to increased bile acid excretion which occurred in all 5 subjects. Nevertheless, the plasma cholesterol concentration fell significantly in only 3. The synthesis of HDL-AI protein fell substantially and was probably responsible for the consistent reduction in plasma apo-AI levels. Thus, probucol appears to enhance LDL-B protein removal and bile acid excretion but inhibits AI protein formation; all these effects may be determined in the small intestine.
Atherosclerosis
PMID:Effects of probucol on low density lipoprotein removal and high density lipoprotein synthesis. 747 Feb


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