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)

Homozygous familial hypercholesterolaemia (FH) is a rare disorder in which the patients develop severe hypercholesterolaemia and premature coronary atherosclerosis from childhood. Here we report a unique family with clustering of homozygous FH. The proband was a 25-year-old man, who showed marked hypercholesterolaemia, multiple xanthomas and severe coronary atherosclerosis. His mother also showed the typical characteristics of homozygous FH. Sequencing analysis of the low-density lipoprotein receptor gene revealed that he was a compound heterozygote, carrying two different point mutations. One was a novel mutation, FH Wakayama (Cys-->Ser at 317), derived from his mother, and the other was a recurrent mutation, FH Niigata (T-->C at 1845 + 2, 5' splice signal in intron 12), derived from his father. The proband we report seems to be a very rare case of an FH homozygote born from a homozygous mother.
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PMID:A compound heterozygote for familial hypercholesterolaemia with a homozygous mother. 856 89

Several investigators have reported that feeding a semi-synthetic diet of casein and dextrose to New Zealand White (NZW) rabbits will increase total serum cholesterol concentration, principally through an increase in the beta-lipoprotein fractions, thereby creating a useful model for atherosclerosis research. Although there is evidence to suggest that the dextrose/casein diet alters low-density lipoprotein receptor and bile acid clearance of cholesterol, the underlying mechanism is not completely understood. The effects of the diet on the overall physiology of the rabbit have received little attention. In this study feeding a diet of casein and dextrose of male NZW rabbits for 4 weeks resulted in changes in the serum lipid concentrations. During that time the rabbits fed the dextrose/casein diet gained less weight than did control rabbits. In the test diet rabbits, liver aspartate and alanine transaminase activities were increased from baseline values of 27 +/- 2 U/L and 89 +/- 9 U/L respectively to 112 +/- 21 U/L and 281 +/- 34 U/L respectively, then returned to the high end of the reference range. Necropsy findings included hepatomegaly caused by vacuolar hepatopathy in 19 or 20 experimental rabbits; rabbits fed the control diet had no hepatic lesions. Ultrastructural analysis revealed that enlargement of the liver cells was due to glycogen deposition. Adrenal glands from animals fed the experimental diet had a minimal change in the size of the adrenocortical cells consisting of slight ballooning and rarefaction of the cytoplasm. In a second study the level of dietary fiber was doubled. This resulted in a three-fold increase in lipid concentrations, compared with the fivefold increase in the first study. The liver enzyme activities were increased to the same extent as in the first study. Histologic changes were comparable to those in the first study. The activity of hepatic cholesterol 7alpha-hydroxylase was 3.7 +/- 0.4 pmol/min/mg of protein, compared with the control value of 7.7 +/- 1.1 pmol/min/mg of protein (P < 0.05) in the second study. The improved rate of weight gain and the lesser increase in total serum cholesterol concentration in the second study with increased dietary fiber suggest that two separate activities may be involved. Although the level of dietary fiber may be related to weight gain and total serum cholesterol values, the relation to the decrease in liver transaminase activities in study 1 was probably coincidental. It appears that the dextrose/casein diet causes decreased activity of hepatic cholesterol 7alpha-hydroxylase, which could cause a decrease in the biliary excretion of cholesterol.
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PMID:Hepatic and adrenal changes in rabbits associated with hyperlipidemia caused by a semi-synthetic diet. 874 27

Apolipoprotein E plays a central role in clearance of lipoprotein remnants by serving as a ligand for low-density lipoprotein and apolipoprotein E receptors. Three common alleles (apolipoprotein E(2), E(3) and E(4)) give rise to six phenotypes. Apolipoprotein E(3) is the ancestral form. Common apolipoprotein E isoforms derive from nucleotide substitutions in codons 112 and 158. Resulting cysteine-arginine substitutions cause differences in: affinities for low-density lipoprotein and apolipoprotein E receptors, low-density lipoprotein receptor activities, distribution of apolipoprotein E among lipoproteins, low-density lipoprotein formation rate, and cholesterol absorption. Accompanying changes in triglycerides, cholesterol and low-density lipoprotein may promote atherosclerosis development. Over 90% of patients with familial dysbetalipoproteinaemia have apolipoprotein E(2)/E(2). Apolipoprotein E(4) may promote atherosclerosis by its low-density lipoprotein raising effect. Establishment of apolipoprotein E isoforms may be important for patients with diabetes mellitus and several non-atherosclerotic diseases. Apolipoprotein E phenotyping exploits differences in isoelectric points. Isoelectric focusing uses gels that contain pH 4-7 ampholytes and urea. Serum is directly applied, or prepurified by delipidation, lipoprotein precipitation or dialysation. Isoelectric focusing is followed by immunofixation/protein staining. Another approach is electro- or diffusion blotting, followed by protein staining or immunological detection with anti-apolipoprotein E antibodies and an enzyme-conjugated second antibody. Apolipoprotein E genotyping demonstrates underlying point mutations. Analyses of polymerase chain reaction products are done by allele-specific oligonucleotide probes, restriction fragment length polymorphism, single-stranded conformational polymorphism, the primer-guided nucleotide incorporation assay, or denaturating gradient gel electrophoresis. Detection with primers that either or not initiate amplification is performed with the amplification refractory mutation system. Disparities between phenotyping and genotyping may derive from isoelectric focusing methods that do not adequately separate apolipoprotein E posttranslational variants, storage artifacts or faint isoelectric focusing bands.
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PMID:Clinical chemistry of common apolipoprotein E isoforms. 886 54

We describe the clinical, biochemical, and genetic features of a patient with true homozygous familial hypercholesterolemia due to the D558N low-density lipoprotein receptor gene mutation, previously designated FH Cincinnati-4. Functional flow-cytometric analysis of the LDL receptorR protein on upregulated EBV-transformed lymphocytes indicated reduction of the number of receptors on the cell surface by 87% and reduction of receptor activity by 89% compared to control cells. With drugs and a portacaval shunt operation, performed when the patient was 15 years old, serum cholesterol was reduced from about 28 to about 15 mmol/l. He died at the age of 32 of a myocardial infarction. The autopsy showed generalized atherosclerosis, especially in the coronary arteries, which were severely stenosed proximally. A rare finding was a large intracranial xanthoma that apparently had been asymptomatic.
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PMID:Phenotypic characterization of a patient homozygous for the D558N LDL receptor gene mutation. 900 29

The low-density lipoprotein receptor (LDLr) plays a pivotal role in cholesterol homeostasis. Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis. To date almost 300 mutations have been identified in the LDLR gene. To facilitate the mutational analysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database (currently listing 210 entries) have been created.
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PMID:Software and database for the analysis of mutations in the human LDL receptor gene. 901 31

The effect of alcohol feeding on the development of atherosclerosis was investigated in low-density lipoprotein receptor gene-knockout (LDLR-/-) mice. Eight-week-old male mice were pair-fed atherogenic liquid diets containing ethanol at different levels (w/v; group A, 5%; group B, 2.5%; and group C, 0%). Tissue sections of the heart were stained with Oil Red O to examine for fatty lesions in proximal aorta. Results showed that the lesion size of group A was 70% smaller than group C after 6 weeks. By contrast, the lesion size of group B was not significantly different from that of group C. Serum high-density lipoprotein-apolipoprotein A1 (apo A1) A1 in LDLR-/- mice was suppressed by feeding the atherogenic diet, but the decrease was negated by alcohol (both groups A and B). The effectiveness of 5% alcohol to protect against atherosclerosis waned with time, but was still noticeable at 12 weeks, even though serum apo A1 remained high. Serum apolipoprotein E was increased by the high fat diet, but not altered by alcohol in the diet. Our data, therefore, show that: (1) alcohol-feeding impedes early atherosclerosis in LDLR-/- mice (this effect of alcohol is dose-dependent); (2) the protective effect of alcohol is not entirely attributable to an elevated serum high-density lipoprotein-apo A1; and (3) severe impairment of lipoprotein metabolism due to a lack of low-density lipoprotein receptors can eventually overwhelm the protective effect of alcohol against atherosclerosis.
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PMID:Alcohol feeding impedes early atherosclerosis in low-density lipoprotein receptor knockout mice: factors in addition to high-density lipoprotein-apolipoprotein A1 are involved. 904 67

Atherogenesis is a complex process that involves the contributions of several pathophysiological sub-systems. The dissection of the genetic component of atherosclerosis has become possible using current molecular technologies and analytical methods. Genetic factors are considered to determine the limits under which atherosclerosis develops and environmental factors are considered to position an individual's risk within these limits. Atherosclerosis proceeds through a well-characterized series of pathological stages that involve key cell types and the expression of particular gene products. Reductionist experimental models have helped to produce a list of several hundred candidate genes for the study of the genetic component of atherosclerosis. Within certain families and isolated communities the effect of a single candidate gene upon atherosclerosis susceptibility may be profound, as in the case of mutations in the gene encoding the low-density lipoprotein receptor, which produce familial hypercholesterolemia and premature atherosclerosis. However, particular candidate genes have small effects on atherosclerosis or to one of its intermediate phenotypes, in whole populations. In addition, pleiotropy and epistasis can confound the identification of the genetic component of atherosclerosis. Despite these limitations, it might still be possible to use genetic information clinically in order to classify individuals who are susceptible to atherosclerosis, especially if as yet undiscovered candidate genes are found to be important determinants of disease. However, it will be impossible to predict the onset of a clinical manifestation of atherosclerosis in a particular person. This is due to the confounding influence of other forces, such as variations in interindividual environmental landscape, non-linear interactions between genes and environment, and even the possible influence of biological chaos.
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PMID:The genetic basis of atherosclerosis. 914 22

Pseudo type III (PT-III) dyslipoproteinemia is characterized by a plasma accumulation of triglyceride-rich lipoproteins (TRL) and their remnants. It mimics type III, but its etiology can not be ascribed to a genetic apo E defect. In order to determine whether PT-III is associated with a genetic lipoprotein receptor abnormality, we have measured (in cultured fibroblasts from affected and nonaffected individuals) the in vitro activity of three lipoprotein receptors which are implicated in the catabolism of TRL, namely the low-density lipoprotein receptor (LDL-R), the lipoprotein receptor-related protein (LRP) and the lipolysis-stimulated receptor (LSR). Specific cell association and degradation of 125I-LDL by LDL-R-upregulated PT-III fibroblasts was not significantly different from that of control cells (103 +/- 10% and 98 +/- 17% of controls; 20 microg/ml 125I-LDL). Specific cell association and degradation of rabbit 125I-beta-VLDL was also not significantly different. LRP activity was assessed by measuring the ability of PT-III and control cells to bind three different LRP ligands: activated alpha2-macroglobulin (alpha2M-MA), lactoferrin and apo E-enriched rabbit beta-VLDL. No significant differences were observed (24.0 +/- 2.1 vs. 23.4 +/- 5.7 fmol/mg for 5 nM of 125I-alpha2M-MA; 4.8 +/- 0.3 vs. 5.2 +/- 1.3 microg/mg for 20 microg/ml of 125I-lactoferrin; 319.4 +/- 51.2 vs. 309.5 +/- 23.2 ng/mg for 5 microg/ml of 125I-beta-VLDL, PT-III vs. control, respectively). LSR activity, as assessed by the cell association or degradation of 125I-LDL by fibroblasts in the presence of 0.5 mM oleate and human leptin, was also not different. No evidence was obtained for deficient cellular recognition of PT-III TRL (d < 1.006 g/ml) by normal human fibroblasts or mouse macrophages. These results suggest that PT-III dyslipoproteinemia is not due to an accumulation in plasma of poorly recognized TRL, nor due to a genetic defect in LDL-R, LRP or LSR.
Atherosclerosis 1997 Jul 11
PMID:Pseudo type III dyslipoproteinemia is associated with normal fibroblast lipoprotein receptor activity. 924 63

Atherogenesis is a complex process that involves the contributions of several pathophysiological subsystems. The dissection of the genetic component of atherosclerosis has become possible using current molecular technologies and analytical methods. Genetic factors are considered to determine the limits under which atherosclerosis develops and environmental factors are considered to position an individual's risk within these limits. Atherosclerosis proceeds through a well-characterized series of pathological stages that involve key cell types and the expression of particular gene products. Reductionist experimental models have helped to produce a list of several hundred candidate genes for the study of the genetic component of atherosclerosis. Within certain families and isolated communities, the effect of a single candidate gene on atherosclerosis susceptibility may be profound, as in the case of mutations in the gene encoding the low-density lipoprotein receptor, which produce familial hypercholesterolemia and premature atherosclerosis. However, particular candidate genes have small effects on atherosclerosis, or to one of its intermediate phenotypes, in whole populations. In addition, pleiotropy and epistasis can confound the identification of the genetic component of atherosclerosis. Despite these limitations, it might still be possible to use genetic information clinically in order to classify individuals who are susceptible to atherosclerosis, especially if as-yet undiscovered candidate genes, which are found to be important determinants of disease. However, it will be impossible to predict the onset of a clinical manifestation of atherosclerosis in a particular person. This is due to the confounding influence of other forces, such as variations in interindividual environmental landscape, nonlinear interactions between genes and environment, and even the possible influence of biological chaos.
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PMID:Candidate genes, small effects, and the prediction of atherosclerosis. 2291 91

To clarify the role of type I and type II macrophage scavenger receptors (MSR-A) in the progression of diet-induced atherosclerosis, we generated mice lacking both MSR-A and low-density lipoprotein receptor (LDLR). After 4 or 12 weeks of a high-fat diet, the sizes of atherosclerotic lesions in MSR-A/LDLR double knockout mice were significantly reduced (p < 0.05) compared with those in LDLR single knockout mice. However, atherosclerotic lesions mainly composed of foamy macrophages were still observed in double knockout mice. Formation of atherosclerotic lesions in double knockout mice was partially explained by the participation of scavenger receptors other than MSR-A such as MARCO, CD36, and macrosialin/CD68. These receptors were clearly demonstrated in the atherosclerotic lesions in double knockout mice as well as LDLR single knockout mice by immunohistochemistry or by reverse transcriptase-polymerase chain reaction. Because the very low density lipoprotein (VLDL) fraction was elevated in the double and single knockout mice, we further examined the possibility that VLDL may participate in foam cell formation in atherosclerotic lesions. When incubated with VLDL isolated from LDLR-deficient mice, cholesterol ester accumulation and foamy transformation occurred in MSR-A-deficient macrophages as well as in normal macrophages. These data indicate that MSR-A plays an essential role in the development of diet-induced atherosclerosis. It also appears that other scavenger receptors, such as MARCO, CD36, and macrosialin/CD68, as well as uptake of VLDL are involved in foam cell formation during atherogenesis in MSR-A/LDLR double knockout mice.
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PMID:Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice. 956 87


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