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)

Tangier disease (TD), caused by mutations in the gene encoding ATP-binding cassette 1 (ABCA1), is a rare genetic disorder in which homozygotes have a marked deficiency of high density lipoproteins (HDL), as well as concentrations of low density lipoproteins (LDL) that are typically 40% of normal. Although it is well known that the reduced levels of HDL in TD are due to hypercatabolism, the mechanism responsible for the low LDL levels has not been defined. Recently, it has been reported that intestinal cholesterol absorption is altered in ABCA1 deficient mice, suggesting that aberrant cholesterol metabolism may contribute to the LDL reductions in TD. In order to explore this possibility, as well as to define the role that ABCA1 plays in the metabolism of apolipoprotein (apoB)-containing lipoproteins, we determined the kinetics of apoB-100 within lipoproteins, and cholesterol absorption, biosynthesis, and turnover, in a compound heterozygote for TD. The levels of HDL cholesterol, LDL cholesterol and LDL apoB-100 in this subject were 7, 27 and 69% of normal, respectively, the latter of which was due to a two-fold increase in LDL catabolism (0.54 vs. 0.26+/-0.07 poolsday(-1)) relative to controls (n=11). NMR analysis of plasma lipoproteins revealed that 91% of the LDL cholesterol in the TD subject was contained within small, dense LDL, as compared with only 20% for controls (n=70). Cholesterol absorption was 97% of the value for controls (n=15) in the TD subject, at 45%, with cholesterol synthesis and turnover increased modestly by 17 and 25%, respectively. Our data are consistent with the concept that the reductions of LDL observed in TD are due to enhanced catabolism, secondary to changes in LDL composition and size, with neither cholesterol absorption nor metabolism significantly influenced by mutations in ABCA1.
Atherosclerosis 2001 Nov
PMID:Cholesterol and apolipoprotein B metabolism in Tangier disease. 1168 26

Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many patients. Development of alternative therapies remains important for patients with adverse reactions to conventional therapy, with defects in the LDL receptor-dependent lipoprotein uptake pathway and for intervention in children. Editing of apoB mRNA by the enzyme APOBEC-1 changes a glutamine codon to a stop codon, leading to the synthesis and secretion of apoB48-containing VLDL, which are rapidly cleared before they can be metabolized to LDL. Human liver does not edit apoB mRNA because it does not express APOBEC-1. Although initially promising, enthusiasm for apobec-1 gene therapy for hypercholesterolemia was blunted by the finding that uncontrolled transgenic expression of APOBEC-1 led to nonspecific editing of mRNAs and pathology. We demonstrate that APOBEC-1 fused to TAT entered primary hepatocytes, where it induced a transient increase in mRNA editing activity and enhanced synthesis and secretion of VLDL containing apoB48. Protein transduction of APOBEC-1 transiently stimulated high levels of apoB mRNA editing in a dose-dependent manner without loss of fidelity. These results suggested that apoB mRNA editing should be re-evaluated as a LDL-lowering therapeutic target in the new context of protein transduction therapy.
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PMID:Apolipoprotein B mRNA editing and the reduction in synthesis and secretion of the atherogenic risk factor, apolipoprotein B100 can be effectively targeted through TAT-mediated protein transduction. 1180 50

Apolipoprotein B (apoB) mRNA editing involves site-specific deamination of cytidine to form uridine, resulting in the production of an in-frame stop codon. Protein translated from edited mRNA is associated with a reduced risk of atherosclerosis, and hence the protein factors that regulate hepatic apoB mRNA editing are of interest. A human protein essential for apoB mRNA editing and an eight-amino acid-longer variant of no known function have been recently cloned. We report that both proteins, henceforth referred to as ACF64 and ACF65, supported APOBEC-1 (the catalytic subunit of the editosome) equivalently in editing of apoB mRNA. They are encoded by a single 82-kb gene on chromosome 10. The transcripts are encoded by 15 exons that are expressed from a tissue-specific promoter minimally contained within the -0.33-kb DNA sequence. ACF64 and ACF65 mRNAs are expressed in both liver and intestinal cells in an approximate 1:4 ratio. Exon 11 is alternatively spliced to include or exclude 24 nucleotides of exon 12, thereby encoding ACF65 and ACF64, respectively. Recognition motifs for the serine/arginine-rich (SR) proteins SC35, SRp40, SRp55, and SF2/ASF involved in alternative RNA splicing were predicted in exon 12. Overexpression of these SR proteins in liver cells demonstrated that alternative splicing of a minigene-derived transcript to express ACF65 was enhanced 6-fold by SRp40. The data account for the expression of two editing factors and provide a possible explanation for their different levels of expression.
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PMID:Two proteins essential for apolipoprotein B mRNA editing are expressed from a single gene through alternative splicing. 1181 17

Hypocholesterolemia and hypotriglyceridemia during the first days of myocardial infarction (MI) is a result of enhanced absorption of saturated fatty acids in the form of triglycerides within very low density lipoproteins (VLDL) through apoE/B-100 receptors. This is followed by inhibition of this endocytosis, accumulation of saturated fatty acids VLDL in the blood, and hypertriglyceridemia. Permanent level of double bonds in MI (ozone titration) results not from MI but from blocking of cell absorption of polyenic fatty acids in the form of cholesterol polyesters in low-density lipoproteins (LDL) through apoB-100 receptors, which is characteristic of atherosclerosis. High molar ratio of double bonds/cholesterol in comparison with the double bonds/glycerol ratio indicates that the majority of polyenic fatty acids in the blood lipoproteins present as cholesterol polyesters. Lipoprotein transfer and cell absorption of saturated fatty acids alone are selectively impaired in MI. Selective impairment of cell absorption of saturated or polyenic fatty acids alone or a combination of both is observed in some diseases. Ozone titration of serum lipid double bonds reflects impaired absorption of essential polyenic fatty acids by cells.
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PMID:[The content of double bonds in blood serum lipids from patients with myocardial infarction]. 1184 Aug 26

In this study, we investigated the effect of atorvastatin, an HMG-CoA reductase inhibitor and CL277082, an ACAT inhibitor, on apolipoprotein B48 synthesis, degradation and secretion in transformed human intestinal enterocytes (CaCo2 cells). Cells were incubated with atorvastatin or CL277082 in the absence or presence of sterol containing media and pulsed with [S35]-methionine and chased with unlabelled methionine. Concomitantly, the effect of atorvastatin and CL277082 on the relative amount of apoB48 protein in cells and media was also quantified by western blotting using an apoB antibody and enhanced chemiluminescence. Suppression of cholesterol synthesis with atorvastatin did not attenuate the production or secretion of apoB48 from CaCo2 cells under basal conditions. On the other hand, suppression of cholesterol biosynthesis with atorvastatin under stimulatory conditions accelerated the degradation of apoB48 in cells without affecting its synthesis or secretion. There was no effect of exogenous sterols on apoB48 secretion. Taken together, neither endogenous nor exogenous cholesterol appears to acutely modulate apoB48 secretion from intestinal cells. In contrast, inhibition of cholesterol esterification with ACAT inhibitor significantly attenuated apoB48 secretion under basal and stimulatory conditions by a mechanism which enhanced apoB48 degradation. Collectively, our results suggest that in CaCo2 cells, newly synthesized cholesterol ester may be an immediate regulator apoB48 secretion.
Atherosclerosis 2002 Mar
PMID:Cholesterol esters regulate apoB48 secretion in CaCo2 cells. 1188 17

Atherosclerosis is remarkably increased in type 2 diabetes suggesting that mechanisms causing arterial lesion are enhanced by the metabolic disturbances of insulin resistance (IR) and diabetes. Several lines of research suggest that processes taking place in the arterial intima extracellular matrix may be part of a shared pathogenic mechanism. The intima extracellular matrix is where atherogenesis takes place. This layer contains fibrilar macromolecules like collagens, proteoglycans (PGs), hyaluronate, and extracellular multi-domain proteins. Specific interaction of lysine, arginine-rich segments of the apoB-100 lipoproteins, LDL, IDL and Lp (a), with the negatively charged glycosaminoglycans (GAGs) of PGs cause retention of the lipoproteins, one of the initiation process of atherogenesis. Such interactions cause structural modifications of the lipid and protein moieties of the lipoproteins that appear to increase their susceptibility to proteases, phospholipases and free radical-mediated processes. The association of apoB-lipoproteins, specially small and dense LDL, with intima PGs increases their uptake by macrophages and human arterial smooth muscle cells (HASMC) leading to 'foam cell' formation. In vitro, elevated levels of non-esterified fatty acids (NEFA) alter the matrix of endothelial cells basement membrane making them more permeable to macromolecules. NEFA cause changes in the expression of genes controlling the PGs composition of the PGs secreted by HASMC causing formation of a matrix with high affinity for LDL. These results lead us to speculate that an important component of the dyslipidemia of IR and type 2 diabetes, chronic high NEFA, may contribute to cellular alterations that cause changes of the arterial intima extracellular matrix. Such changes may increase the atherogenicity of the retention of apoB lipoproteins in the intima and contribute to the systemic alteration of the arterial wall frequently observed in IR and type 2 diabetes.
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PMID:The extracellular matrix on atherogenesis and diabetes-associated vascular disease. 1204 79

Previously we cloned the human macrophage apolipoprotein B-48 receptor (ApoB-48R) and documented its expression in human atherosclerotic foam cells (1). Now we have identified and characterized the murine macrophage apob-48r cDNA gene sequence and its chromosomal location. The cDNA (3,615 bp) -deduced amino acid (aa) sequence (942 aa) is approximately 45% identical to the human macrophage APOB-48R, but not to other known gene families. The murine Apob-48r gene, like the human APOB-48R gene, consists of four exons interrupted by three small introns and is syntenically located on chromosome 7. Functionally significant conserved domains include an N-terminal hydrophobic domain, a glycosaminoglycan attachment site, an N-glycosylation site, and an ExxxLL internalization motif C-terminal to the putative internal transmembrane domain. Two conserved coiled-coil domains are likely involved in the spontaneous homodimerization that generates the active dimeric ligand binding species (mouse, approximately 190 kDa; human, approximately 200 kDa). Transfection of the murine apoB-48R into Chinese hamster ovary cells (CHOs) confers apoB-48R function: rapid, high-affinity, specific uptake of known triglyceride-rich lipoprotein ligands of the apoB-48R and, of note, uptake of the cholesteryl ester-rich apoB-48-containing very low density lipoproteins that accumulate in atherosclerosis-prone apoE-deficient mice. Uptake of these ligands by murine apoB-48R-transfected CHOs causes saturable, visible cellular triglyceride and cholesterol accumulation in vitro that resemble foam cells of atherosclerotic lesions. In aggregate, the data presented here and that previously published suggest that the apoE-independent murine apoB-48R pathway may contribute to the spontaneous development of atherosclerotic lesions rich in macrophage-derived foam cells observed in apoE-deficient mice, a murine model of human atherosclerosis.
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PMID:The murine macrophage apoB-48 receptor gene (Apob-48r): homology to the human receptor. 1217 62

Diffuse intimal thickening (DIT) that develops as a physiologic adaptation in the arterial wall has been implicated to have a predilection for atherosclerosis. We histologically investigated the lipid accumulation process in the human coronary DIT by focusing on the localization of normal and oxidized low-density lipoproteins (LDLs). Immunohistochemistry for apolipoprotein B 100 (a major apolipoprotein of LDL) and 8-iso-prostaglandin F(2alpha) (an oxidative product in LDL) showed substantial accumulation of oxidized relative to normal LDLs in the deep layers of DIT (52/139 segments). Subendothelial deposition of normal rather than oxidized LDLs, known as an early event of fatty streak formation, was less frequently found (13/139 segments). In contrast with fibrofatty lesions, lipid accumulation localized deep in DIT was characterized by fine lipid droplets scattered in the preserved tissue and by its association with neither macrophage accumulation nor apoptosis in the constituent cells. On the other hand, the deep intimal location of lipid accumulation clearly coincided with increased type I and type III collagen and elastic fibers but rarely with sulfated proteoglycans including decorin, which were all strongly expressed in advanced lesions. This lipid accumulation was found only in sites with DIT of more than 200 micro m, occasionally extending to the inner media and involving neovessel formation around it. The presence of deep intimal lipid accumulation was associated with reduced endothelium-dependent relaxation to substance P in isolated coronary rings. These results suggest that normal and oxidized LDLs accumulate preferably in the nutritional border zone of established DIT involving local extracellular matrix alterations but independently of inflammatory or apoptotic processes. This may contribute to the functional and morphologic abnormalities seen in human coronary atherogenesis that progresses slowly with age.
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PMID:Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary arteries. 1237 78

To determine the molecular basis of familial hypercholesterolemia (FH) in Japan, 200 unrelated patients with clinically diagnosed heterozygous FH were screened for mutations in coding and promoter region of the low density lipoprotein (LDL) receptor gene using denaturing gradient-gel electrophoresis (DGGE), DNA sequencing and Southern blotting analysis. About 37 different mutations in the LDL receptor gene were identified in 125 (62.5%) of the patients, 22 of these mutations have not been described before. The most common mutations were K790X (19.5%), P664L (6.0%), FH-Tonami-1 (6.0%), IVS15-3C>A (5.5%) and FH-Tonami-2 (4.5%), whereas the other mutations were rare. No apolipoprotein B (apoB) mutations responsible for familial ligand-defective apoB-100 (FDB) were identified. Polymorphisms of apolipoprotein E (apoE) and scavenger receptor class B type I (SR-BI) were observed to have minor effects on the lipid and lipoprotein profile. In 75 (32.5%) of the FH patients, LDL receptor gene mutations could not be identified. These patients had significantly lower total cholesterol (7.71+/-1.64 vs. 8.68+/-1.47 mmol/l, P<0.001) and LDL-cholesterol (6.02+/-1.51 vs. 6.87+/-1.47 mmol/l, P<0.001) in plasma, also a lower incidence of coronary heart disease (CHD) (22 vs. 29%, P=0.05) compared with patients with a LDL receptor gene mutation, suggesting that besides LDL receptor, defect of other genes involved in LDL metabolism may be a cause of FH with a milder phenotypic expression in Japanese population.
Atherosclerosis 2002 Dec
PMID:Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population. 1241 85

Glycosaminoglycans (GAGs) bound to various proteoglycans (PGs) present in the cardiovascular system have been proposed to perform a wide range of functions. These include conferring viscoelastic properties; interacting with and modulating growth factors and enzymes; and as receptors and co-receptors in lipoprotein metabolism. Binding of apoB-100 lipoproteins, particularly low density lipoproteins (LDL), to GAGs of extracellular matrix PGs in arteries has been proposed to be an initiating event in development of atherosclerosis. This study was initiated with the aim of getting an overview of the binding patterns of different lipoprotein subclasses with individual GAG categories. We thus evaluated the interaction of lipoproteins with GAGs commonly found in the cardiovascular system using a gel mobility-shift assay developed for this purpose. The same procedure was used to measure lipoproteins binding to metabolically [(35)S]-labeled whole PGs prepared from three cell types, arterial smooth muscle cells, THP-1 macrophages and from HepG2 cells. The effect of GAG composition on PGs on lipoprotein binding was evaluated by enzymatic degradation of the carbohydrate chains. Heparan sulfate was found to bind beta very low density lipoproteins (beta-VLDL) and a chylomicron remnant model (beta-VLDL+apoE), but not LDL. Dermatan sulfate was found to bind LDL, but not beta-VLDL or the chylomicron remnant model. Chondroitin sulfate and heparin were found to bind all lipoproteins tested (LDL, beta-VLDL and beta-VLDL+apoE) although with different affinities. We can conclude that each lipoprotein subclass tested binds a specific assortment of the GAGs tested. The observations made contribute to the understanding of new and complex mechanisms by which carbohydrate and lipid metabolism may be linked.
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PMID:Glycosaminoglycan-lipoprotein interaction. 1244 68


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