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)

Dietary lipid, following incorporation into chylomicrons, is rapidly removed from the blood by a two-stage process. Most of the triglyceride is taken up by extrahepatic tissue, particularly muscle and adipose tissue. The residual triglyceride and virtually all of the cholesterol ester is removed by the liver through the clearance of a particle called a chylomicron remnant. The remarkable rapidity and specificity of uptake of this particle seems to be due to its acquisition of apoE in the plasma. Uptake is mediated in part by the LDL receptor, the LRP (alpha a-macroglobulin receptor), and perhaps by a sieving mechanism that leads to trapping, but not endocytosis. Uptake is modulated by the type of apoE inherited, the amount of apoC present on the particle, and, perhaps, the phospholipid and fatty acyl chain composition of the particle. The process may be slowed in diabetes and hypothyroidism. The metabolic effects of the particle can be variable, depending on the composition of the diet, and this can affect whole body cholesterol metabolism significantly. Furthermore, even moderately prolonged residence of these particles in the circulation could contribute in a significant way to atherogenesis. Thus, the remnant particle and its uptake by the liver may be important links in determining the dietary contribution to the rate of atherosclerosis.
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PMID:Hepatic clearance of plasma chylomicron remnants. 133 75

Atherosclerotic lesions are composed of a complex mixture of cell types that are engorged with lipid and enveloped in extracellular matrix elements. This manifestation probably results from imbalances in the cellular processing of cholesterol-delivering lipoproteins, changes in extracellular matrix deposition, and growth factor elaboration. One receptor class that could modulate these processes is LDL receptor-related protein/alpha 2-macroglobulin receptors (LRP/alpha 2-MR). Consequently, the presence of LRP/alpha 2-MR was determined on a temporal basis in lesions of distinct morphologies that were developed in cholesterol-fed New Zealand and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. The two strains of rabbits developed similar degrees of hypercholesterolemia in response to 0.5% wt/wt cholesterol in their diet. Lipoprotein-cholesterol distribution was also similar in the two strains. Aortic intimal areas covered by grossly discernible atherosclerotic lesions were extensive and not statistically different between the strains. Despite the similarities in the extent of hypercholesterolemia, lipoprotein distribution, and extent of atherosclerosis, the cellularity of the lesions formed was different in the two groups. Atherosclerotic lesions in cholesterol-fed New Zealand rabbits were uniformly rich in macrophages and deficient in smooth muscle cells, as determined by immunocytochemical staining with the cell-specific monoclonal antibodies RAM-11 and HHF-35. In contrast, atherosclerotic lesions formed in cholesterol-fed heterozygous WHHL rabbits covered a spectrum ranging from macrophage-rich lesions to those predominantly composed of disaggregated smooth muscle cells that were embedded in dense layers of extracellular matrix.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Presence of LDL receptor-related protein/alpha 2-macroglobulin receptors in macrophages of atherosclerotic lesions from cholesterol-fed New Zealand and heterozygous Watanabe heritable hyperlipidemic rabbits. 752 98

The data described in this chapter demonstrate that the metabolic control of processes responsible for the formation, uptake and clearance of remnant particles is considerably more complex than previously believed. It now appears that several interacting reactions are involved in the process, and evidence is accumulating that defects in any one of these reactions may severely affect the optimal metabolic cascade. Proper exposure of receptor-binding domains in apoE and perhaps apoB-100 molecules is mandatory. Lipoprotein lipase-induced triglyceride hydrolysis is essential and responsible for the formation of remnant particles from secreted triglyceride-rich lipoproteins. The existence of apoE molecules that exhibit normal function is important but perhaps not always essential. Sequestration in the liver through lipoprotein lipase and/or apoE-mediated binding to heparan sulphate ('bridging' effect) appears to play an exceedingly important role during the early phase of the remnant clearance process. The 'bridging' is responsible not only for sequestration in the liver but also for enhanced uptake and lysosomal degradation of the particles. At this stage, association with the remnants of newly secreted, liver-derived apoE molecules may occur and add to the affinity of the particles towards receptors, especially if the new apoE molecules are inserted in a favourable conformational configuration. A role for the hepatic lipase has been suggested but is yet to be proved. Finally, it should be emphasized that remnants are cleared from the plasma predominantly, if not exclusively, following interaction with cellular receptors. Although the LDL receptor avidly internalizes remnant particles and is apparently active in species with a low LDL concentration (e.g. mice and rats), a second specialized and specific receptor or receptors must exist. Whether the LRP is the only remnant receptor or other, as yet unidentified, receptor proteins are also present, remains to be established. Data published in the last few years have begun to elucidate the interactions and consequences of the many reactions and proteins that are involved with the metabolism of remnant lipoproteins. More is to be learned, including the association of remnants in processes that lead to initiation/progression of atherosclerosis.
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PMID:Remnant particles and their metabolism. 859 23

White Carneau pigeons develop atherosclerosis naturally, and at an accelerated rate with cholesterol feeding. Macrophages play a central role in the pathogenesis of atherosclerosis in pigeons, as they do in man. The purpose of this study was to determine whether pigeon macrophages express the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2 MR/LRP) and whether this receptor would recognize beta-VLDL, the major cholesterol-transporting lipoprotein in cholesterol-fed pigeons. The binding of 125I-methylamine-treated alpha 2M (125I-alpha 2 M+) at 4 degrees C was saturable (> 10 nM), specific, Ca2+ dependent, was competed for by the receptor-associated protein (RAP), and had a Kd of binding of 1-5.6 nM, similar to mouse peritoneal macrophages studied simultaneously. At 37 degrees C the bound 125I-alpha 2 M+ was rapidly internalized and degraded in lysosomes. The binding of alpha 2 M+ was not down-regulated with cholesterol loading, as is the LDL receptor on pigeon macrophages. At 4 degrees C there was no competition for binding of 125I-alpha 2 M+ by either pigeon or rabbit beta-VLDL, nor was binding of 125I-pigeon or rabbit beta-VLDL competed for by alpha 2 M+. Stimulation of cholesterol esterification by rabbit or pigeon beta-VLDL was unaffected by RAP, lactoferrin, or alpha 2 M+. Metabolism of 125I-pigeon or rabbit beta-VLDL was not competed by RAP, lactoferrin, or alpha 2 M+ even in the presence of lipoprotein lipase. Pigeon macrophages, and a 500 kDa membrane protein isolated from them, were recognized by several antihuman alpha 2 MR/LRP monoclonal antibodies. The 500 kDa membrane protein also bound 45Ca. These data suggest considerable sequence homology with the human alpha 2 MR/LRP. This is the first study to characterize a functional alpha 2 MR/LRP on peritoneal macrophages from an avian species. There was no evidence, however, that the alpha 2 MR/LRP mediates uptake of beta-VLDL by pigeon macrophages.
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PMID:Characterization of alpha 2-macroglobulin receptor low density lipoprotein receptor-related protein (alpha 2 MR/LRP) in White Carneau pigeon peritoneal macrophages: its role in lipoprotein metabolism. 903 Jan 94

The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) has been postulated to participate in a number of diverse physiological and pathological processes ranging from the homeostasis of plasma lipoproteins, atherosclerosis, and fibrinolysis to neuronal regeneration and survival. It has not been possible to demonstrate in vivo the physiological significance of LRP for each of these complex processes by a conventional gene knockout approach because LRP is essential for embryonic development. Here we have used the Cre/loxP recombination system to achieve inducible, tissue-specific and quantitative disruption of the LRP gene in adult mice. Inactivation of LRP in the livers of LDL receptor-deficient mice resulted in the accumulation of cholesterol-rich remnant lipoproteins in the circulation. In normal animals, this caused a compensatory upregulation of the LDL receptor in the liver. Conditional gene targeting has thus allowed us to isolate a specific physiological function of LRP for in vivo analysis and has provided unequivocal evidence for another LDL receptor-independent cholesterol clearance pathway in liver.
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PMID:Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. 944 4

The low density lipoprotein (LDL) receptor-related protein (LRP) is a cell receptor that has close structural homology to the LDL and very low density lipoprotein receptors and thus is believed to play an important role in lipid metabolism. This study was carried out to evaluate the distribution of a known tetranucleotide repeat polymorphism in the LRP gene and its association with serum lipoprotein-lipid and apolipoprotein levels in four large samples comprising Hispanics (n=373) and non-Hispanic Whites (n=522) from the U.S. and Nigerian Blacks from Sokoto (n=390) and Benin (n=800). A total of four alleles, designated 83, 87, 91 and 95 bp, were observed. The 83 bp allele was observed at 0.4-1.1% in the two U.S. populations but was completely absent in African Blacks. Sokoto Blacks had significantly different frequencies of the 87 and 91 bp alleles compared to Hispanics (P=0.008) and non-Hispanic Whites (P=0.024). The frequency of the 91 bp allele was also significantly higher in Benin Blacks compared to Hispanics (P=0.026) and non-Hispanic Whites (P=0.054). The analysis of the relationship between the LRP polymorphism and serum lipid traits yielded some significant race and gender specific significant association for lipoprotein(a) in non-Hispanic White males (P=0.02); HDL2-cholesterol in Hispanic females (P=0.03) and apolipoprotein B in Benin males (P=0.04). We also observed an interaction between the LRP polymorphism and menopausal status for Lp(a) in Hispanic females (P=0.014). However, considering multiple comparisons were performed, these associations could be due to chance. Our data indicate that although the LRP tetranucleotide polymorphism exhibits inter-racial differences in its distribution, it does not appear to have a significant role in affecting serum lipid traits.
Atherosclerosis 1998 Mar
PMID:Racial differences in the distribution of a low density lipoprotein receptor-related protein (LRP) polymorphism and its association with serum lipoprotein, lipid and apolipoprotein levels. 956 51

Chylomicron and VLDL are triglyceride-rich lipoprotein particles assembled by the intestine and liver respectively. These particles are not metabolized by the liver in their native form. However, upon entry into the plasma, their triglyceride component is rapidly hydrolyzed by lipoprotein lipase and they are converted to cholesterol-rich remnant particles. The remnant particles are recognized by the liver and rapidly cleared from the plasma. This process is believed to occur in two steps. (i) An initial sequestration of remnant particles on hepatic cell surface proteoglycans, and (ii) receptor-mediated endocytosis of remnants by hepatic parenchymal cells. The initial binding to proteoglycans may be facilitated by lipoprotein lipase and hepatic lipase which possess both lipid- and heparin-binding domains. The subsequent endocytic process may be mediated by LDL receptors and/or LRP. Both receptors have a high affinity for apoE, a major apolipoprotein component of remnant particles. The lipases may also serve as ligands for these receptors. An impairment of any component of this complex process may result in an accumulation of remnant particles in the plasma leading to atherosclerosis and coronary heart disease.
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PMID:Receptor-mediated mechanisms of lipoprotein remnant catabolism. 1020 55

The low-density lipoprotein (LDL) receptor (LDL-R) family consists of cell-surface receptors that recognize extracellular ligands and internalize them for degradation by lysosomes. The LDL-R is the prototype of this family, which also contains very-low-density lipoprotein receptors (VLDL-R), apolipoprotein E receptor 2, LRP, and megalin. The family members contain four major structural modules: the cysteine-rich complement-type repeats, epidermal growth factor precursor-like repeats, a transmembrane domain, and a cytoplasmic domain. Each structural module serves distinct and important functions. These receptors bind several structurally dissimilar ligands. It is proposed that instead of a primary sequence, positive electrostatic potential in different ligands constitutes a receptor binding domain. This family of receptors plays crucial roles in various physiologic functions. LDL-R plays an important role in cholesterol homeostasis. Mutations cause familial hypercholesterolemia and premature coronary artery disease. LDL-R-related protein plays an important role in the clearance of plasma-activated alpha 2-macroglobulin and apolipoprotein E-enriched lipoproteins. It is essential for fetal development and has been associated with Alzheimer's disease. Megalin is the major receptor in absorptive epithelial cells of the proximal tubules and an antigenic determinant for Heymann nephritis in rats. Mutations in a chicken homolog of VLDL-R cause female sterility and premature atherosclerosis. This receptor is not expressed in liver tissue; however, transgenic expression of VLDL-R in liver corrects hypercholesterolemia in experiment animals, which suggests that it can be a candidate for gene therapy for various hyperlipidemias. The functional importance of individual receptors may lie in their differential tissue expression. The regulation of expression of these receptors occurs at the transcriptional level. Expression of the LDL-R is regulated by intracellular sterol levels involving novel membrane-bound transcription factors. Other members of the family are not regulated by sterols. All the members are, however, regulated by hormones and growth factors, but the mechanisms of regulation by hormones have not been elucidated. Studies of these receptors have provided important insights into receptor structure-function and mechanisms of ligand removal and catabolism. It is anticipated that increased knowledge about the LDL-R family members will open new avenues for the treatment of many disorders.
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PMID:The mammalian low-density lipoprotein receptor family. 1044 20

Type III hyperlipoproteinemia (HLP) is a genetic disorder characterized by accumulation of remnant lipoproteins in the plasma and development of premature atherosclerosis. Although receptor binding-defective forms of apolipoprotein (apo) E are the common denominator in this disorder, a number of apparent paradoxes concerning its pathogenesis still exist. However, studies in transgenic animals are resolving the mechanisms underlying this disorder. PARADOX I: Defective apoE (commonly apoE2) is essential but not sufficient to cause overt type III HLP. In fact, most apoE2 homozygotes are hypolipidemic. Studies in apoE2 transgenic models have demonstrated the impact of other genes or hormones in converting the hypolipidemia to hyperlipidemia. PARADOX II: Among apoE2 homozygotes, men are more susceptible than women to type III HLP. Transgenic studies have shown that estrogen affects both LDL receptor expression and lipolytic processing, explaining the resistance of women to this disorder until after menopause. PARADOX III: ApoE deficiency is associated with hypercholesterolemia, whereas the type III HLP phenotype is characterized by both hypercholesterolemia and hypertriglyceridemia. The hypercholesterolemia is caused by impaired receptor-mediated clearance, whereas the hypertriglyceridemia is caused primarily by impaired lipolytic processing of remnants and increased VLDL production associated with increased levels of apoE. PARADOX IV: ApoE2 is associated with recessive inheritance of this disorder, whereas other defective apoE variants are associated with dominant inheritance. Determinants of the mode of inheritance are the differential binding of apoE variants to the LDL receptor versus the HSPG/LRP complex and the preference of certain apoE variants for specific lipoproteins. Thus, the pathogenesis of this sometimes mysterious disorder has been clarified.
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PMID:Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. 1055 97

The low density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional receptor involved in numerous biological processes relevant to vascular biology including lipoprotein metabolism. Several polymorphisms in the LRP gene have been described and in this study we examined their influence on coronary artery disease (CAD). We compared the frequencies of the exon 3 (C766T), exon 6 (C663T), exon 22 (C200T), and four rarer and more recently described polymorphisms in approximately 600 Caucasian subjects aged <50 years with angiographic CAD and approximately 700 similarly aged subjects without symptomatic CAD randomly selected from the community. We found the distribution of exon 22 C200T genotypes to differ significantly between the CAD (CC: 52%, CT: 39%, TT: 9%) and control subjects (CC: 43%, CT: 46%, TT: 11%, P=0.005), with the CC genotype conferring an odds ratio (OR) for CAD of 1.5 (95% CI: 1.2-1.8, P=0.001) despite a lack of significant influence on plasma cholesterol or triglyceride. The other LRP polymorphisms were less common. Two showed an association with CAD; for the exon 3 C766T polymorphism the TT genotype was significantly lower (1.0 vs. 2.7%; OR: 0.36; P=0.04) and, for the exon 6 C663T polymorphism, the heterozygote frequency was higher (6.2 vs. 3.4%; OR: 1.9; P=0.03) in CAD subjects. In conclusion, LRP gene polymorphisms, particularly the relatively common exon 22 C200T polymorphism, are a significant risk factor for premature CAD in Caucasians.
Atherosclerosis 2003 May
PMID:Influence of exonic polymorphisms in the gene for LDL receptor-related protein (LRP) on risk of coronary artery disease. 1273 94


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