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)

Apolipoprotein E is a secretory glycoprotein that associates with lipoprotein particles and is coded for by a single locus on chromosome 19. The three common allelic isoforms of this protein (apo E2, apo E3 and apo E4) are associated with distinct patterns of lipoprotein metabolism and variable risks for coronary artery disease. In addition, recent work has shown that the presence of the apo E4 isoform constitutes a major risk for developing late-onset Alzheimer's disease as well as hypercholesterolaemia. The only differences between these isoforms result from cysteine-arginine interchanges at codons 112 and 158. There is considerable disagreement in the literature concerning the identity of the ancestral allele. In order to resolve this, 24 chimpanzees and individuals from a number of other primate species were analysed. All were similar to apo E4. This suggests that apo E4 is the ancestral allele and that apo E2 and apo E3 arose after the split of the human and chimpanzee lineages.
Atherosclerosis 1995 Jan 06
PMID:Arginine residues at codons 112 and 158 in the apolipoprotein E gene correspond to the ancestral state in humans. 777 71

Apolipoprotein E (apoE) is a major constituent of plasma lipoprotein that functions in lipid transport and redistribution (reverse cholesterol transport) and probably plays an important role in inhibiting the development and/or progression of atherosclerosis. While cis-acting regions involved in basal and tissue-specific control of the apoE gene have been identified by promoter mapping studies, much less is known about factors that regulate the gene. In this study, we demonstrate that the region between -94 and -84 upstream of transcriptional start site of the human apoE gene contains a binding site for the transcriptional repressor factor BEF-1, a tyrosine-phosphorylated nuclear protein that was first identified in HeLa cells. Using gel retardation assays, we show that HeLa cell-derived BEF-1 binds the apoE BEF-1 homology, and this binding can be competed with the prototype BEF-1 sequence, but not by a mutated sequence. Furthermore, we demonstrate that the apoE- producing human liver HepG2 cell produces significant levels of BEF-1, which could bind to both the prototype BEF-1 sequence and the apoE homology, and be competed equivalently with cold BEF-1 or apoE homology. To determine if BEF-1 affected the expression of apoE, we performed competition experiments using plasmids containing the intact or mutated BEF-1 homology. The introduction of the intact BEF-1 site into HepG2 cells resulted in an induction of apoE mRNA, whereas control and mutated BEF-1-containing plasmids had no significant effect. We also found that increasing the level of nuclear BEF-1 by treatment of cells with orthovanadate resulted in a reduction in the level of apoE mRNA. Overall, our data suggest that the endogenous apoE gene in the human HepG2 cell line is repressed by the trans-acting influence of nuclear factor BEF-1.
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PMID:The human apolipoprotein E gene is negatively regulated in human liver HepG2 cells by the transcription factor BEF-1. 779 34

Apolipoprotein E deficiency leads to familial dysbetalipoproteinemia characterized by increases in serum lipid levels, atherosclerosis, and cutaneous xanthoma. Apolipoprotein E is synthesized in many tissues in the body, including the epidermis. In the present study, we determined whether transgenic mice deficient in apolipoprotein E develop cutaneous xanthoma and the effect of dietary fat intake on these lesions. We also determined whether apolipoprotein E-deficient mice have abnormalities in cutaneous barrier function or stratum corneum structure. Homozygous apolipoprotein E-deficient mice (-/-) fed a high-fat diet displayed a diffuse inflammatory infiltrate in the dermis surrounding fat droplets in macrophages. In homozygous mice (-/-) fed a low-fat diet, similar lesions were seen but they tended to be focal and less prominent. In heterozygous mice (+/-) fed the high-fat diet, a few inflammatory cells were present in the dermis but foam cells were not seen. Control mice (+/+) fed a high-fat diet displayed scattered inflammatory cells in the dermis. Heterozygous mice (+/-) fed a low-fat diet were similar to control mice (+/+) fed a low-fat diet. The extent of foam cell formation correlated directly with the degree of atherosclerosis. There were no abnormalities in permeability-barrier function or stratum corneum structure in apolipoprotein E-deficient mice. Thus, the lack of apolipoprotein E production in the epidermis does not appear to lead to any detectable abnormality in structure or function of the stratum corneum. However, lack of apolipoprotein E leads to cutaneous foam cell formation, presumably secondary to disturbances in lipoprotein metabolism.
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PMID:Apolipoprotein E deficiency leads to cutaneous foam cell formation in mice. 782 81

Apolipoprotein E (apoE) is one of the major protein constituents of chylomicron and very-low-density lipoprotein (VLDL) remnants and plays a central role as a ligand in the receptor-mediated uptake of these particles by the liver. Including the most common variant, apoE3, 30 apoE variants have been characterized. At present, 14 apoE variants have been found to be associated with familial dysbetalipoproteinemia, a genetic lipid disorder characterized by elevated plasma cholesterol and triglyceride levels and an increased risk for atherosclerosis. Seven apoE variants were found to be associated with other forms of hyperlipoproteinemia. This report presents an overview of all currently known apoE variants and their effects on lipoprotein metabolism.
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PMID:Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. 783 47

Conventional coronary risk factors have not consistently been found to be related to restenosis after coronary angioplasty. Apolipoprotein E (apo E) gene polymorphism and/or plasma apo(a) levels were determined in 195 subjects undergoing prospective follow up and angiographic study 6 months after elective balloon angioplasty of a previously untreated coronary obstruction. Restenosis (stenosis > or = 50% plus loss of > or = 50% of initial gain) had occurred in 59 of 150 subjects for whom E genotypes were available. The apo epsilon 4 allele frequency in those with restenosis was higher than those without (0.20 vs. 0.10, P < 0.01), attributable to an excess of epsilon 4 homozygotes in the restenosis group (5 of 59 vs. 1 of 91, P < 0.04). Restenosis was not related to plasma apo(a) and the apo epsilon 4 allele was not associated with elevated levels of apo(a) as has been reported elsewhere. No relationship was found between E genotype and serum lipid and lipoprotein levels; paradoxically, LDL cholesterol was significantly lower and HDL cholesterol higher in those with restenosis. In conclusion, homozygosity for apolipoprotein epsilon 4 appears to be an important determinant of restenosis after coronary angioplasty.
Atherosclerosis 1994 Oct
PMID:Apolipoprotein epsilon 4 homozygosity--a determinant of restenosis after coronary angioplasty. 784 69

Apolipoprotein E (apo E) is one of the apolipoprotein components in very low density lipoproteins (VLDL) and high density lipoproteins (HDL). Apo E binds to low density lipoprotein (LDL) receptors and apo E-specific remnant receptors, and regulates remnant lipoprotein metabolism through these receptors in the liver. In the general population, apo E shows genetic heterogeneity, with three alleles (epsilon 4, epsilon 3, and epsilon 4) which produce apo E isoproteins, apo E4, apo E3, and apo E2, respectively. Apo E2 is defective in its binding to lipoprotein receptors, resulting in the accumulation of lipoprotein remnants in the plasma. Type III hyperlipoproteinemia appears in a few percent of the individuals who are homozygous for apo E2 and the development of hyperlipoproteinemia requires the presence of other genetic or environmental factors. Even heterozygous individuals with apo E2 or apo E4 differ from those with only apo E3 in plasma lipoprotein metabolism. Subjects with an E3/2 phenotype had reduced LDL and increased VLDL levels, and those with an E4/3 phenotype had increased LDL levels in serum. In addition to these common apo E isoproteins, there are several unique mutants of apo E, which are associated with hyperlipoproteinemia and atherosclerosis.
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PMID:[Apolipoprotein E]. 785

Apolipoprotein E (apoE) deficiency causes severe hyperlipidemia and atherosclerosis in humans and in gene-targeted mice. Although the majority of apoE in plasma is of hepatic origin, apoE is synthesized by a variety of cell types, including macrophages. Because macrophages derive from hematopoietic cells, bone marrow transplantation was used to examine the potential of apoE synthesized by bone marrow-derived cells to correct the hyperlipidemia and atherosclerosis caused by apoE deficiency. After transplantation of bone marrow from mice with the normal apoE gene into apoE-deficient mice, apoE was detected in serum and promoted clearance of lipoproteins and normalization of serum cholesterol levels. ApoE-deficient mice given transplants of normal bone marrow showed virtually complete protection from diet-induced atherosclerosis.
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PMID:Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. 786 32

Apolipoprotein E (apo E)-deficient mice are severely hypercholesterolemic and develop advanced atheromas independent of diet. The C57BL/6 strain differs from most inbred strains by having lower HDL concentrations and a high risk of developing early atherosclerotic lesions when fed an atherogenic diet. The relative HDL deficiency and atherosclerosis susceptibility of the C57BL/6 strain are corrected with the expression of a human apolipoprotein AI (apo AI) transgene in this genetic background. To examine if increases in apo AI and HDL are also effective in minimizing apo E deficiency--induced atherosclerosis, we introduced the human apo AI transgene into the hypercholesterolemic apo E knockout background. Similar elevations of total plasma cholesterol occurred in both the apo E knockout and apo E knockout mice also expressing the human apo AI transgene. The latter animals, however, also showed a two- to threefold increase in HDL and a sixfold decrease in susceptibility to atherosclerosis. This study demonstrates that elevating the concentration of apo AI reduces atherosclerosis in apo E deficient-mice and suggests that elevation of apo AI and HDL may prove to be a useful approach for treating unrelated causes of heightened atherosclerosis susceptibility.
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PMID:Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. 804 Mar 45

Apolipoprotein E (apo E) is a polymorphic glycoprotein that plays an essential part in the binding to receptors for the uptake of chylomicrons and VLDL remnants and of LDL. The three major isoforms are E3 (Cys112/Arg158), E4 (Arg112/Arg158) and E2 (Cys112/Cys158). The apo E genetic variation has a great impact. In most of type III familial hyperlipoproteinemias (HLP), E2 is implicated at the homozygote status. In other cases, rare alleles are directly responsible for dominant type III HLP. Apo E polymorphism is an essential determinant in the interindividual variations of lipids in healthy subjects in various populations. Its influence can be significant on the efficacy of nutritional or therapeutic interventions. The allele epsilon 4 appears to be associated with an increased risk of premature atherosclerosis. Recently, epsilon 4 was demonstrated to be associated with an early Alzheimer's disease onset. Apo E polymorphism contributes to the lipid disorders in diabetes and obesity. The analysis of apo E polymorphism can be carried out with two conceptually different approaches. The first one is based on the separation of plasma isoforms of the protein by isoelectric focusing or bidimensional electrophoresis. The other one consists in the application of molecular biology techniques (PCR and endonuclease restriction profiles) for a detection of the common alleles and of several rare alleles, avoiding the possible errors of the phenotyping technique of the apo E protein. The application of genetic engineering allows a better understanding of the role played by apo E towards its receptors and in other molecular interactions which are not well known up to now.
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PMID:[Pathology of the human apolipoprotein E gene]. 807 81

Apolipoprotein E (apo E) mediates both lipid accumulation by and removal from cells and may be secreted by both macrophages and smooth muscle cells in vitro, but its cellular source in atherosclerotic plaques is not known. Lipoprotein lipase (LPL) also enhances cell lipid accumulation and is synthesized by macrophage foam cells in atherosclerotic plaques. To determine the cellular source of apo E in human coronary atherosclerotic lesions and its relationship to LPL synthesis, in situ hybridization and immunohistochemistry were performed on 12 atherosclerotic plaques and six nondiseased coronary artery segments from 10 cardiac transplant recipients. Apo E messenger RNA was localized to both non-foam cell and foam cell macrophages in plaques, but not to other cell types, and was not detected in nonatherosclerotic arteries. Half of the regions with non-foam cell macrophages expressed neither apo E nor LPL messenger RNA, whereas 86% of macrophage foam cell-containing regions contained both messenger RNAs. Polyclonal antisera raised against human apo E localized apo E protein to the surface of macrophages and surrounding matrix in plaques but not in control coronary segments. An LPL-specific monoclonal antibody demonstrated that, similar to apo E, LPL protein on foam cell and non-foam cell macrophages was detected in atherosclerotic lesions, but LPL was also localized to intimal muscle smooth muscle cells and was not distributed as widely in association with matrix as was apo E. The expression of both apo E and LPL in atherosclerotic lesions but not in normal intima suggest that these molecules play a role in lipid metabolism in atherosclerosis.
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PMID:Apolipoprotein E localization in human coronary atherosclerotic plaques by in situ hybridization and immunohistochemistry and comparison with lipoprotein lipase. 812 39


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