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)

Certain proteins (called apolipoproteins B and E) on the surface of lipoprotein particles are responsible for mediating the binding of cholesterol-rich particles to specific lipoprotein receptors on the surface of cells and represent a major pathway controlling blood cholesterol levels. Three important disorders of lipoprotein metabolism, which provide insights into the molecular mechanisms responsible for the elevation of specific atherogenic lipoproteins, are the following: (1) Type III hyperlipoproteinemia results from specific mutations in apolipoprotein E that prevent the normal binding of chylomicron remnants and very-low-density lipoprotein remnants to lipoprotein receptors. Patients with this disorder who have elevated levels of these remnant lipoproteins develop atherosclerosis. (2) Familial defective apolipoprotein B-100 results from a single amino acid substitution in apolipoprotein B that prevents low-density lipoprotein from binding normally to the low-density lipoprotein receptor and elevates plasma cholesterol levels. (3) Familial hypercholesterolemia, which results in elevated levels of plasma low-density lipoprotein and premature atherosclerosis, is caused by a variety of mutations in the low-density lipoprotein receptor that interfere with the normal binding of lipoproteins to this receptor. These observations not only provide insights into the mechanisms responsible for normal lipoprotein metabolism, but also highlight the potential role of specific lipoproteins in atherogenesis.
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PMID:Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism. 184 76

The Watanabe heritable hyperlipidemic (WHHL) rabbit reproduces human familial hypercholesterolemia due to a congenital low-density lipoprotein receptor deficiency and is characterized by elevated serum LDL cholesterol levels and early atherosclerosis. We attempted to transplant normal allogeneic hepatocytes into WHHL rabbits without chronic immunosuppression to cure the LDL receptor-deficient state. Livers from normal New Zealand White (NZW) rabbits were digested by intraportal perfusion of collagenase solution. Pure hepatocytes (PH) were obtained by Percoll gradient separation and nonparenchymal (NP) liver cells by pronase digestion. PH and NP were incubated with fluorescein isothiocyanate-monoclonal anti-rabbit class I, anti-class II, and anti-T cell antibodies and subjected to flow cytometry analysis. PH and NP were also used as stimulators in one way mixed lymphocyte-hepatocyte cultures (MLHC), before and after ultraviolet B light (UVB) exposure. Intraportal and intrasplenic injection of allogeneic PH were also performed in homozygous WHHL rabbits. PH were attached to collagen-coated dextran microcarriers (mc-PH) for intraperitoneal injection. Recipient control and transplanted WHHL rabbits received a single dose of cyclosporine subcutaneously (10 mg/kg/s.c.) at the time of transplantation. PH were mainly class I-positive (77.6%) and class II-negative (5.9%), while 31.5% of NP cells were class II-positive. In MLHC, PH did not stimulate proliferation, (stimulation index: 0.97 +/- 0.21), unlike NP (SI: 23.7). This latter response was abrogated by prior exposure of NP to UVB light. Intraportal injection of PH (n = 4) reduced serum LDL cholesterol to 60% of baseline, an effect lasting 2-3 weeks, and dose-dependent. Intraperitoneal mc-PH, 4 x 10(8) (n = 4), reduced serum LDL cholesterol levels to 45% of baseline more than 4 weeks posttransplant (P = 0.04). We conclude that transplantation of normal allogeneic NZW rabbit mc-PH reduces serum LDL cholesterol levels in homozygous WHHL rabbits without chronic immunosuppression. Longitudinal studies will establish if less atherosclerosis develops in mc-PH WHHL recipients than sham controls.
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PMID:Hepatocyte transplantation for the low-density lipoprotein receptor-deficient state. A study in the Watanabe rabbit. 214 23

Apolipoprotein B (apoB) is the major protein component of low-density and very-low-density lipoproteins. We have recently isolated nonoverlapping cDNA clones for apoB and confirmed their identity by sequence comparisons. We now report the mapping of the human apoB gene (APOB) to the p23-p24 region of chromosome 2 by examination of human-mouse somatic cell hybrids and by in situ hybridization to human chromosomes. Thus, APOB is unlinked to members of the dispersed gene family encoding other apolipoprotein species or to the gene encoding the low-density lipoprotein receptor. Hybridization analysis with genomic DNA and liver and intestinal mRNA suggests that APOB encodes both the high-molecular-weight form of apoB (apoB100) incorporated into very-low-density lipoproteins in liver and the lower-molecular-weight form (apoB48) incorporated into chylomicrons in intestine. Restriction fragment length polymorphisms of APOB have been identified and should prove useful in examining the possibility that genetic variations of APOB are involved in dyslipoproteinemias and atherosclerosis.
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PMID:Human apolipoprotein B: chromosomal mapping and DNA polymorphisms of hepatic and intestinal species. 301 97

Effect of cholestyramine treatment in early life of Watanabe heritable hyperlipidemic rabbits (an animal model lacking low-density lipoprotein receptor activity) on subsequent (6 months recovery) occurrence of natural atherosclerotic lesion and arterial cholesterol metabolism was investigated. Initial cholestyramine treatment decreased both plasma total cholesterol and HDL-cholesterol levels which normalized within 4 weeks after treatment was discontinued. At 9 months of age (age of occurrence of spontaneous atherosclerotic lesions), the extent of aortic atherosclerosis in cholestyramine pre-treated animals was modestly lower (P less than 0.05), as compared to controls, with a significant (P less than 0.05) decrease in aortic cholesteryl ester content. Furthermore, at the end of the recovery period aortic activity of acyl-CoA: cholesterol acyltransferase and neutral cholesterol esterase activity was significantly (P less than 0.05) lower in cholestyramine-pretreated animals. These studies show that early cholestyramine pre-treatment in a low-density lipoprotein receptor-deficient animal model causes persistent changes which might influence cholesteryl ester accumulation and atherogenesis in adult life, even after cholestyramine treatment is discontinued.
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PMID:Cholestyramine treatment in early life of low-density lipoprotein receptor deficient Watanabe rabbits: decreased aortic cholesteryl ester accumulation and atherosclerosis in adult life. 360 80

It is now clear that hypercholesterolemia can, in some instances, be a necessary and sufficient cause of premature atherosclerosis. This has been best established in patients with familial hypercholesterolemia, a deficiency of the low-density lipoprotein receptor. Although hypercholesterolemia is not the only cause of atherosclerosis, a large body of evidence has identified it as a determining cause in many cases. This article reviews current hypotheses regarding the mechanisms by which hypercholesterolemia accelerates atherogenesis. The role of the foam cell is discussed in detail because it is a characteristic feature of the earliest lesion, the so-called fatty streak. Once thought to derive exclusively from smooth muscle cells, the foam cell is now known to originate in large part from monocytes that enter the artery wall and alter their properties to become tissue macrophages. Recent studies of the biology of the macrophage-derived foam cell are providing new insights into the mechanisms by which it enters the arterial wall and interacts with various classes of native and modified lipoproteins. As our understanding of the biology of the foam cell and its precursors grows, it may become possible to intervene and slow the progress of atherosclerosis by new modalities that might act synergistically with measures to control plasma cholesterol levels.
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PMID:Lipoproteins and the pathogenesis of atherosclerosis. 362 17

The low-density lipoprotein (LDL) receptor plays a central role in mammalian cholesterol metabolism, clearing lipoproteins which bear apolipoproteins E and B-100 from plasma. Mutations in this molecule are associated with familial hypercholesterolemia, a condition which leads to an elevated plasma cholesterol concentration and accelerated atherosclerosis. The N-terminal segment of the LDL receptor contains a heptad of cysteine-rich repeats that bind the lipoproteins. Similar repeats are present in related receptors, including the very low-density lipoprotein receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor, and in proteins which are functionally unrelated, such as the C9 component of complement. The first repeat of the human LDL receptor has been expressed in Escherichia coli as a glutathione S-transferase fusion protein, and the cleaved and purified receptor module has been shown to fold to a single, fully oxidized form that is recognized by the monoclonal antibody IgG-C7 in the presence of calcium ions. The three-dimensional structure of this module has been determined by two-dimensional NMR spectroscopy and shown to consist of a beta-hairpin structure, followed by a series of beta turns. Many of the side chains of the acidic residues, including the highly conserved Ser-Asp-Glu triad, are clustered on one face of the module. To our knowledge, this structure has not previously been described in any other protein and may represent a structural paradigm both for the other modules in the LDL receptor and for the homologous domains of several other proteins. Calcium ions had only minor effects on the CD spectrum and no effect on the 1H NMR spectrum of the repeat, suggesting that they induce no significant conformational change.
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PMID:Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor. 760 91

The application of methods to create transgenic mice in which a gene of interest is either overexpressed or genetically inactivated has provided us with an ever-growing number of animal models to study complex physiological processes in vivo. Analysis of these mouse models has increased our knowledge about basic mechanisms that control biological systems and the pathological processes in human genetic disorders. This review focuses on the analysis of mouse models in which individual components of the hepatic clearance pathway for plasma lipoproteins have been inactivated. These studies have demonstrated that two hepatic lipoprotein receptors, the low-density lipoprotein receptor and the low-density lipoprotein receptor-related protein operate jointly in the uptake of dietary lipoproteins from the circulation. These findings have important implications for our understanding of pathophysiological processes resulting in hyperlipoproteinemia and atherosclerosis in patients.
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PMID:Animal models for disorders of hepatic lipoprotein metabolism. 767 Sep 24

Familial hypercholesterolemia is an autosomal dominant disorder caused by a mutation of the gene for the low-density lipoprotein receptor and is characterized by rapidly progressing coronary atherosclerosis. We assessed the long-term results of coronary artery bypass grafting performed during the past 13 years in 62 patients with heterozygous familial hypercholesterolemia, whose mean plasma total and low-density lipoprotein cholesterol level was 327 mg/dl, respectively. The patients had severe coronary atherosclerosis, with coronary stenosis index of 19.7, and the prevalence of extracoronary atherosclerotic lesions was 27%. Sixty-one patients underwent successful coronary artery bypass operation, with an average of 2.5 grafts, and the coronary stenosis index decreased to 7.1. After operation, all patients consumed a cholesterol-lowering diet and received drug therapy with pravastatin, probucol, or cholestyramine. Seven patients who were resistant to drug therapy were treated with plasma low-density lipoprotein apheresis. The cholesterol-lowering therapy reduced plasma total cholesterol level by 37%, low-density lipoprotein cholesterol level by 42%, and low-density lipoprotein/high-density lipoprotein cholesterol ratio by 37% (p < 0.001). During the follow-up period (mean, 52 months; range, 10 to 157 months), there was no cardiac death, but three patients died of malignant disease. The actuarial survival rate was 95% at 5 years and 89% at 12 years after operation. The actuarial freedom from recurrent angina was 90% at 5 years and 53% at 11 years after operation. Four patients underwent reoperation, an average of 8 years postoperatively, because of vein graft atherosclerosis. In spite of severe coronary atherosclerosis, these patients with familial hypercholesterolemia showed good long-term outcome after coronary artery bypass operation. The present findings suggest that aggressive use of arterial grafts, intensive cholesterol-lowering drug therapy, and low-density lipoprotein apheresis may be useful in patients with familial hypercholesterolemia.
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PMID:Coronary artery bypass grafting in familial hypercholesterolemia. 785 88

Glycoprotein 330 (gp330) is a member of a family of receptors with structural similarities to the low-density lipoprotein receptor. Gp330 is expressed by a number of specialized epithelia, including renal proximal tubules, where it can mediate endocytosis of ligands such as complexes of urokinase and the serpin, plasminogen activator inhibitor-1. Gp330 has also been shown to bind in vitro to lipoprotein lipase and apolipoprotein E-enriched beta VLDL, suggesting a role for this receptor in lipoprotein metabolism. The 39-kDa protein, referred to as receptor associated protein (RAP), binds to and copurifies with gp330 and antagonizes the ligand binding activity of gp330. In this paper, we report the use of homology-PCR cloning to isolate cDNAs encoding human gp330. Using gp330 cDNA and previously isolated human RAP cDNA probes, we performed fluorescence in situ hybridization to map the human chromosomal location of the genes for these proteins. The gene for gp330 was mapped at a single site on the long arm of human chromosome 2 on the border of bands 2q24-q31. The gene for RAP was mapped to the short arm of human chromosome 4 at position 4p16.3, which is in the region of the chromosomal deletion causing Wolf-Hirschhorn syndrome. The assignment of chromosomal map positions for gp330 and RAP genes will aid in the evaluation of their potential roles in human diseases such as Wolf-Hirschhorn syndrome and disorders of lipoprotein metabolism, such as atherosclerosis.
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PMID:Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1). 795 95

The low-density lipoprotein receptor-related protein (LRP) is a multifunctional receptor that binds to apolipoprotein E-rich lipoproteins, lipoprotein lipase, alpha 2-macroglobulin, lactoferrin, and tissue plasminogen activator. We studied the mRNA expression of LRP in human monocyte-derived macrophages and THP-1 cells. mRNA expression of LRP was induced during cell differentiation from human monocytes to macrophages or after incubation with phorbol ester (tetradecanoylphorbol acetate 100 ng/mL) in THP-1 cells, and the addition of 30 ng/mL macrophage colony-stimulating factor further enhanced LRP expression. These results indicated that the expression of LRP depended on the stage of differentiation and maturation of monocytic cells. mRNA expression of LRP was also enhanced in human monocyte-derived macrophages in the presence of acetylated low-density lipoprotein and in aorta of rabbits fed a high-cholesterol diet. We hypothesize that the LRP induced in monocyte-derived macrophages is involved in the initial process of atherosclerosis by interacting with its multiple ligands.
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PMID:Induction of LDL receptor-related protein during the differentiation of monocyte-macrophages. Possible involvement in the atherosclerotic process. 819 72


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