UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
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Lipoprotein Lp(a) is a plasma lipoprotein which possesses many similarities to low density lipoprotein (LDL) in its physical and chemical properties. The major protein constituent of both lipoproteins is apolipoprotein B100 (apo B100); however, Lp(a) is unique in that it contains an additional distinct antigen, the (a)-antigen, attached to apo B100 by one or more disulphide bridges. The (a)-glycoprotein has recently been shown to have a striking amino-acid sequence homology with plasminogen; so, Lp(a) seems to be a potential bridge between the fields of atherosclerosis and thrombosis. Metabolic studies have made it clear that Lp(a) is not a product derived from other apo B-containing lipoproteins, but is secreted by the liver as a distinct mature lipoprotein. Although a relationship between elevated serum Lp(a) levels and the occurrence of atherosclerotic diseases had been postulated by several investigators, little is known today about the role of this lipoprotein and/or the mechanism whereby it might predispose to atheroma. However, the new knowledge on the structure of Lp(a) being more and more rapidly acquired, should facilitate the understanding of the mechanism of its atherogenicity and its physiopathological role.
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PMID:[Lipoprotein (a). An additional marker of atherosclerosis]. 214 Dec 41

Diets currently used to produce atherosclerotic lesions in mice are often undefined and cause accumulation of fat in the liver and gallstone formation. Therefore, synthetic low and high fat diets of known composition were formulated in this study. A synthetic diet containing 50% sucrose, 15% cocoa butter, 1% cholesterol, and 0.5% sodium cholate was found to produce a depression in high density lipoprotein cholesterol (HDL-C) and an elevation of very low density lipoprotein (VLDL) and low density lipoprotein cholesterol (LDL-C) in the atherosclerosis-susceptible strain, C57BL/6J. This diet was able to consistently produce aortic lesions and led to a decrease in liver damage and gallstone formation. The synthetic low fat diet did not produce HDL-C levels as high as those found in mice fed chow, but resulted in similar VLDL/LDL-C levels. Lipoprotein and apolipoprotein parameters were compared in C57BL/6J and the atherosclerosis-resistant strain, C3H/HeJ, consuming the synthetic low fat or high fat diets. As reported earlier, when consuming a high fat diet C57BL/6J mice have significantly lower HDL-C and apoA-I levels than C3H/HeJ mice. Further analysis shows that the molar ratio of plasma HDL-C to apoA-I is significantly lower in C57BL/6J mice, suggesting that HDL in the susceptible strain has a lower cholesterol-carrying capacity. This conclusion is consistent with the observation that the HDL particle size is smaller for C57BL/6J mice than for C3H/HeJ. Both strains increased their apoE levels when fed the synthetic high fat diet, but C3H/HeJ mice had higher levels of apoE on both diets. The major response to consumption of the high fat diet for both strains was an increase in apoB-48 from 5 micrograms/ml on a low fat diet to 54 and 109 micrograms/ml for C57BL/6J and C3H/HeJ, respectively. ApoB-100 showed minimal response to the high fat diet. The defined high fat diet can be used to study atherosclerosis in the mouse since it produces aortic lesions but reduces or eliminates other pathological changes such as gallstone formation and liver damage.
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PMID:Synthetic low and high fat diets for the study of atherosclerosis in the mouse. 238 Jun 34

The application of molecular biology techniques has enabled us to determine the gene sequence, organization, transcription and processing of apolipoprotein genes. Consequently, new insights have been gained in the biosynthesis and processing of these proteins. In addition to apoA-I, apoA-II and apoC-III reported here, other apolipoprotein genes such as apoC-II and apoE genes were found to share common intron-exon organizations. The results suggest that these genes most probably arise from a common ancestral gene. Utilizing cDNA as hybridization probes, we have localized apoA-I, apoA-II, apoC-II, apoC-III, apoE and apoB to specific locations of individual chromosomes (for review, see ref. 6). There is no clear relationship between currently known physiological function and the organization of the apolipoproteins in the chromosomes with the exception of the LDL receptor and its ligand, apoE which are localized to chromosome 19. However, apoB-100, the major ligand for the LDL receptor is on chromosome 2 and not in synteny with the apoE and the LDL receptor genes. The cloning of the major human apolipoprotein genes have also allowed us to initiate studies on the molecular defects leading to various dyslipoproteinemias including Tangier disease and abetalipoproteinemia. Undoubtedly, information derived from these studies will provide the basis for future in vitro and in vivo studies on patients with dyslipoproteinemia and premature atherosclerosis.
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PMID:The molecular biology of human apoA-I, apoA-II, apoC-II and apoB. 243 61

Human lipoprotein(a) is a low density lipoprotein-like lipoprotein whose concentration in plasma is correlated with atherosclerosis. The characteristic protein component of lipoprotein(a) is apolipoprotein(a) (apo(a)) which is disulfide-linked to apolipoprotein B-100. Sequencing of rhesus monkey apo(a) cDNA suggests that this protein, like human apo(a), is highly similar to plasminogen. Sequence data suggests that a plasminogen-like protease activity and kringle 1-, 2-, 3-, and 5-like domains are unnecessary for apo(a) function, but a highly repeated kringle four-like domain is important. Liver is the major site of apo(a) RNA synthesis; reduced amounts of message were also found in testes and brain. Co-expression with apoB-100 and plasminogen in rhesus tissues is not mandatory.
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PMID:Rhesus monkey apolipoprotein(a). Sequence, evolution, and sites of synthesis. 292 43

Apolipoprotein (apo) B-100 cDNAs were identified in a human liver cDNA library cloned in the expression vector lambda gt11. The beta-galactosidase-apoB-100 fusion protein was detected by two independently produced low density lipoprotein polyclonal antisera and by three apoB-100 monoclonal antibodies that crossreact with apoB-74. It was not recognized by two apoB-100 monoclonal antibodies that crossreact with apoB-26. The longest clone, lambda B8, was completely sequenced. It contains a 2.8-kilobase DNA fragment containing the codons for the carboxyl-terminal 836 amino acid residues of apo-B-100, as well as the 3' untranslated region of apoB-100 mRNA. We have thus mapped apoB-74 to the carboxyl-terminal portion of apoB-100. The deduced amino acid sequence of the cloned DNA matches the sequences of 14 apoB-100 peptides determined in our laboratory. Minor differences in amino acid sequence were noted in three of the peptides, suggesting polymorphism of apoB-100 at the protein and DNA levels. Secondary structure predictions reveal an unusual pattern for apolipoproteins, consisting of beta-structure (24%), alpha-helical content (33%), and random structure (30%). Ten amphipathic helical regions of 10-24 residues were identified. This carboxyl-terminal fragment of apoB-100 is considerably more hydrophobic than other apolipoproteins with known structure. Its lipid binding regions might include stretches of highly hydrophobic beta-sheets as well as amphipathic helices. Our findings on apoB structure might be important for understanding the role of apoB-100-containing lipoproteins in atherosclerosis.
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PMID:Molecular cloning and expression of partial cDNAs and deduced amino acid sequence of a carboxyl-terminal fragment of human apolipoprotein B-100. 293 36

The interaction of plasma lipoproteins with mammalian cells is facilitated by specific receptors on the cell surface. The chylomicron remnant receptor recognises apolipoprotein E (apo E) and mediates the uptake of chylomicron remnants by the liver. The low density lipoprotein (LDL) receptor recognises lipoproteins containing apolipoprotein B100 or an activated form of apo E. The LDL receptor therefore mediates the uptake of intermediate density lipoprotein (IDL) and LDL by the liver, and it also facilitates uptake of LDL by other tissues. A receptor for high density lipoprotein (HDL) has been postulated to permit the interaction of HDL with the cell surface to remove intracellular cholesterol for transport ultimately to the liver. Knowledge of the structure and function of the chylomicron remnant receptor and the HDL receptor is still incomplete, but extensive information about the physiological importance of the LDL receptor is now available. Cells utilise the LDL receptor to take up and degrade LDL to obtain cholesterol for cellular use. In vivo these receptors affect the plasma LDL-cholesterol level by regulating both the synthesis and catabolism of LDL. Genetic mutations that impair LDL receptor function cause familial hypercholesterolaemia (FH). Patients with FH have elevated LDL-cholesterol levels and are at increased risk for the development of atherosclerosis. Patients with heterozygous FH have 1 abnormal and 1 normal allele at the LDL receptor locus; the normal allele enables them to respond to certain cholesterol-lowering medications by producing more LDL receptors. Patients with homozygous FH have 2 mutant alleles at the LDL receptor locus and lack the genetic capacity to produce any normal LDL receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The lipoprotein receptor concept. 307 23

In order to investigate the in vivo function of hepatic lipase, cats were injected with anti-cat hepatic lipase antibodies which produced a complete and specific inhibition of heparin-releasable hepatic lipase. The cat was chosen as an animal model because it displays, like man, a relative deficiency of lipoprotein lipase compared to hepatic lipase and because the possession of two subfractions of high density lipoproteins, HDL2 and HDL3. In fasted cats no changes were observed in plasma triglycerides or phospholipids. In fed animals triglycerides increased considerably, indicating that hepatic lipase may have a function in the postprandial phase. In fat-loaded cats (6 g of fat/kg) triglycerides in the d less than 1.019 g/ml fraction increased from 4 h after the blockade due to accumulation of lipoproteins with pre-beta-mobility containing the apoproteins, apo B-100, apo E and apo A-I. Apo B-48 did not accumulate consistently. Phospholipids in the HDL2-fraction and those in the HDL3-fraction of the fat-loaded cats tended to increase and decrease from 6 and 9 h after the blockade, respectively. The absolute change in HDL2 phospholipids approximated that of HDL3-phospholipids. Overall, the density of HDL particles decreased, apparently secondary to the accumulation of apo A-I in the d less than 1.019 g/ml fraction. Our findings suggest that hepatic lipase is involved in the hydrolysis of a special class of apo A-I containing triglyceride-rich lipoproteins synthesised in the postprandial phase.
Atherosclerosis 1988 Feb
PMID:Studies on the function of hepatic lipase in the cat after immunological blockade of the enzyme in vivo. 312 48

The complete amino acid sequence of the liver-synthesized apolipoprotein B (apoB) species, apoB 100, has been derived from cloned cDNA. The protein consists of 4536 amino acids (+ a 27 amino acid signal sequence). Cysteine is clustered in the N-terminal 1/10 of the protein, suggesting the presence of a stabilized tertiary structure in this part of the molecule. Three types of structure are suggested to be of importance for the binding of the protein to lipids; (i) hydrophobic sequences with a high probability for beta-sheet structure, (ii) strict amphipathic beta-sheets, and (iii) amphipathic alfa-helices. An apoB 100 molecule is completed within 10-14 min and secreted after approximately 30 min, 1/3 of which is due to the transfer through the endoplasmic reticulum (ER), while 2/3 is spent in the Golgi apparatus. ApoB 100 is co-translationally N-glycosylated and 25% of the oligosaccharide chains is processed in the Golgi compartment. Other posttranslational modifications that have been discussed include covalent acylation and phosphorylation. It has also been suggested that the lipid moiety of the apoB 100 lipoproteins are modified during the passage through the Golgi apparatus. The site of lipoprotein assembly is suggested to be separated from the site of apoB 100 synthesis, and apoB 100 appears to be co-translationally bound to the ER membrane and from this transferred to the ER lumen. Based on these observations a model for the assembly of apoB 100 lipoproteins is discussed in this paper. The intestinal derived apoB species, apoB 48, has a molecular mass of 210 kDa and appears to correspond to the N-terminal 48% of apoB 100. The mechanism by which apoB 48 is formed is still not known. Available data indicate that the protein is formed within the intestinal cells, these data also argue against the possibility that apoB 48 is formed by posttranslational proteolysis of apoB 100. The formation of a separate apoB 48 mRNA by alternative splicing has been suggested, based on the observation of a 7 kb mRNA which corresponds to the 5' portion of the apoB 100 mRNA. However, the most abundant apoB mRNA species found in the intestine have a size that corresponds to that of the apoB 100 mRNA, furthermore the observation that apoB 48 appears to terminate in a 7.5 kb exon that appears to lack alternative splice sites, does not favour the possibility of alternative splicing.
Atherosclerosis 1987 Nov
PMID:Apolipoprotein B: structure, biosynthesis and role in the lipoprotein assembly process. 331 51

The heterogeneity of the plasma low-density lipoproteins (LDL) in subjects with type III hyperlipoproteinemia (3 cases), with hypertriglyceridemia (4 cases) and with the heterozygous form of familial hypercholesterolemia (FH, 4 cases) has been evaluated using a new, high resolution equilibrium density gradient ultracentrifugation procedure. The mass distribution profile, physicochemical properties, particle heterogeneity and apoprotein B content of a series of 13 LDL subfractions was examined in the 3 hyperlipidemic groups and the data were compared with those reported earlier in normolipidemic subjects. In FH, LDL mass was distributed as a narrow peak of d approximately 1.031-1.034 g/ml, whereas the distribution in hypertriglyceridemia was markedly asymmetric with a single peak of elevated density (d approximately 1.037-1.043 g/ml); the distribution in type III subjects was distinguished by its bi- or trimodal nature and broad profile. The chemical composition of LDL gradient subfractions in FH and in hypertriglyceridemia markedly resembled that of the respective parent LDL of d = 1.019-1.063 g/ml, displaying elevated proportions of cholesteryl ester in FH and of protein in hypertriglyceridemia. LDL subfractions in type III disease were enriched in free cholesterol. The Stokes diameters of LDL particles in corresponding subfractions from the 3 hyperlipidemic states were similar; however, whereas a single particle species was characteristic of each LDL subfraction in both FH and in our normolipidemic group, 2 species were frequently present in each subfraction in both type III and type IV diseases; in addition, subfractions from type III subjects occasionally exhibited 3 size species. Apolipoprotein B-100 was the predominant protein component in LDL subfractions from all 3 hyperlipidemic groups. Plasma LDL consist then of multiple particle species which constitute a particularly complex spectrum in type III hyperlipoproteinemia and in hypertriglyceridemia. The origin(s) of such particle subspecies is indeterminate at present; moreover, they may differ in their intravascular metabolism, in their degradation in tissues and in their relative atherogenicities.
Atherosclerosis 1988 Jun
PMID:Further resolution and comparison of the heterogeneity of plasma low-density lipoproteins in human hyperlipoproteinemias: type III hyperlipoproteinemia, hypertriglyceridemia and familial hypercholesterolemia. 340 Dec 87

ApoB-100 and apoB-48 may be readily resolved in 3.3% sodium dodecyl sulphate-polyacrylamide gels. This study has characterized the relative chromogenicities (staining intensity/micrograms protein) of human apoB-100 and apoB-48 in various lipoprotein classes with Coomassie Brilliant Blue (R250) upon SDS-PAGE. The relation between dye uptake and the mass of each apoB species in any lipoprotein preparation, was linear at least within the concentration range of total apoprotein B which is optimally resolved in these gels (20-50 micrograms total apoprotein B), and was a function of the density of the particular lipoprotein fraction under investigation. There was a constant and characteristic difference between the chromogenicity for apoB-100 and that for apoB-48 as determined from the slopes of their respective chromogenicity curves. The slope of the lines describing staining intensity vs. protein mass for both apoB-100 and apoB-48 decreased as the density of the lipoprotein fraction increased. The slope of the line for apoB-100 was steeper than that for apoB-48 (i.e. chromogenicity apoB-100 greater than apoB-48) in all lipoprotein fractions where both were present. The relationship between the slopes of the lines for apoB-100 and apoB-48 was constant regardless of the density of the lipoprotein fraction. The chromogenicity curves for apoB-100 and for apoB-48 obtained when lipoprotein samples were applied to gels in concentrations conventionally used for this technique (i.e. 20-100 micrograms total apoB/gel) did not extrapolate to the same point on the ordinate, which precludes the use of a simple ratio or "chromogenicity factor" to describe their relative chromogenicities over this concentration range, Hence, a novel approach was developed to determine the relative mass of apoB-100/apoB-48 in lipoprotein samples, based on their staining characteristics in SDS-PAGE.
Atherosclerosis 1987 May
PMID:The chromogenicity and quantitation of apoB-100 and apoB-48 of human plasma lipoproteins on analytical SDS gel electrophoresis. 360 34

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