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)

Various antihypertensive agents were studied in vitro to determine their effects on cholesterol esterification by arterial ACAT (acylCoA:cholesterol acyltransferase; E.C. 2.3.1.26) and on the activity of plasma LCAT (lecithin:cholesterol acyltransferase; E.C. 2.3.1.43). Propranolol inhibited ACAT in normal rat aorta, atheromatous rabbit aorta, and in isolated microsomes from atheromatous rabbit aorta, and in isolated microsomes from atheromatous rabbit aorta. Inhibition reached 50% in microsomes at approximately 0.8 mM. Metoprolol, prazosin, and chlorthalidone also inhibited microsomal ACAT, but to a lesser extent than propranolol; nadolol had no effect on the enzyme. Propranolol, metoprolol, prazosin, and chlorthalidone also inhibited LCAT in human plasma, whereas nadolol showed no inhibitory effect. Fifty percent inhibition occurred at 2 mM with prazosin and chlorthalidone and at 4-5 mM with propranolol. Metoprolol showed a weak dose-dependent inhibition that ranged from 2 to 10% over the concentration range 0.5-5 mM. The data suggest a mechanistic basis for altered lipoprotein profiles observed clinically with certain antihypertensive therapies and suggest that a direct effect of beta-blockers on arterial wall metabolism may account for their recognized ability to reduce the development of experimental atherosclerosis and to improve survival in post-myocardial infarction patients.
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PMID:Effects of antihypertensive agents propranolol, metoprolol, nadolol, prazosin, and chlorthalidone on ACAT activity in rabbit and rat aortas and on LCAT activity in human plasma in vitro. 241 Jun 71

Lecithin:cholesterol acyltransferase (LCAT) and lysolecithin acyltransferase (LAT) are two activities carried out by the same plasma enzyme, but require different apoprotein activators. The LCAT reaction takes place primarily on high density lipoproteins (HDL) and is activated by serum albumin, whereas LAT takes place on low density lipoproteins (LDL) and is inhibited by albumin. In nephrotic syndrome (NS), the levels of serum albumin are reduced, whereas the LDL levels are increased, and therefore, the ratio of LAT/LCAT activities should be increased. To test this hypothesis, we estimated the lipid levels and the two enzyme activities in experimental NS induced in rats by the injection of anti-Fx1A antibody (passive Heymann nephritis). As found in other nephrotic conditions, the plasma lipid levels rose progressively as the proteinuria increased and the serum albumin concentration declined. In addition, the ratio of LAT/LCAT activities increased by about fourfold after nine days of induction of nephritis. The LCAT activity correlated positively and the LAT activity negatively with serum albumin levels. The esterified cholesterol correlated positively with LCAT activity in normal rats but negatively in nephrotic animals, indicating that most of the cholesteryl esters in NS may be non-LCAT derived. The free cholesterol/lecithin ratio, a known risk factor for atherosclerosis, increased significantly in nephrotic rats. Furthermore, since the increase in the LAT activity produces more disaturated lecithins, another putative risk factor, the cumulative risk of coronary heart disease may be increased in long-term NS.
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PMID:Plasma lipids and acyltransferase activities in experimental nephrotic syndrome. 277 94

Rabbit apolipoprotein A-I (apo A-I) of molecular weight 27,612 contained 241 amino acids. In contrast to its human counterpart which has 3 methionine residues, the rabbit protein possesses only one and therefore produces 2 fragments after CNBr cleavage (CNBr I and II, NH2- and COOH-terminal, respectively). From a series of monoclonal antibodies raised against human apo A-I, 2 (A05 and A16) cross-reacted with rabbit apo A-I. In the present study, we show that A05 recognizes the rabbit CNBr I fragment while the integrity of the intermediate region between the 2 CNBr fragments (including the methionine residue) is required for the expression of the A16 antigenic determinant. Competition experiments were performed between human 125I-labelled high density lipoprotein (HDL) and a variety of preparations of human and rabbit apo A-I (including the purified and delipidated protein, complexes of dimyristoylphosphatidylcholine (DMPC) containing apo A-I, HDL subfractions and whole serum). The A05 antigenic determinant was expressed identically in all these fractions of both species. In contrast the A16 showed poor reactivity with delipidated apo A-I, the apparent affinity constant being about 100 times less than for HDL. These data suggest that phospholipids improve the recognition of apo A-I by the A16 antibody. The similar immunoreactivity of the human and rabbit proteins in the present study is consistent with the view that the NH2-terminal region contains the major portion activating lecithin:cholesterol acyltransferase.
Atherosclerosis 1989 Sep
PMID:Expression, location and cross-reactivity of two antigenic sites on the amino terminal region of rabbit and human apolipoprotein A-I. 280 50

The size of low density lipoproteins (LDL) is strongly correlated with LDL cholesteryl ester (CE) content and coronary artery atherosclerosis in monkeys fed cholesterol and saturated fat. African green monkeys fed 11% (weight) fish oil diets have smaller LDL and less CE per LDL particle than lard-fed animals. We hypothesized that this might be due to a lower plasma lecithin:cholesterol acyltransferase (LCAT) activity in fish oil-fed animals. Using recombinant particles made of egg yolk lecithin-[14C]cholesterol-apoA-I as exogenous substrate, we found no difference in plasma LCAT activity (27 versus 28 nmol CE formed per h/ml) of fish oil- versus lard-fed animals, respectively; furthermore, no diet-induced difference in immunodetectable LCAT was found. However, plasma phospholipids from fish oil-fed animals were over 4-fold enriched in n-3 fatty acids in the sn-2 position compared to those of lard-fed animals. Additionally, the proportion of n-3 fatty acid-containing CE products formed by LCAT, relative to the available n-3 fatty acid in the sn-2 position of phospholipids, was less than one-tenth of that for linoleic acid. The overall rate of LCAT-catalyzed CE formation with phospholipid substrates from fish oil-fed animals was lower (5-50%) than with phospholipid substrates from lard-fed animals. These data show that n-3 fatty acids in phospholipids are not readily utilized by LCAT for formation of CE; rather, LCAT preferentially utilizes linoleic acid for CE formation. The amount of linoleic acid in the sn-2 position of plasma phospholipids is reduced and replaced with n-3 fatty acids in fish oil-fed animals. As a result, LCAT-catalyzed plasma CE formation in vivo is likely reduced in fish oil-fed animals contributing to the decreased cholesteryl ester content and smaller size of LDL particles in the animals of this diet group.
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PMID:The reactivity of plasma phospholipids with lecithin:cholesterol acyltransferase is decreased in fish oil-fed monkeys. 291 20

Measurement of plasma lecithin:cholesterol acyltransferase (LCAT) activity was used to segregate unaffected family members (n = 8) from heterozygotes (n = 8) and homozygotes (n = 2) in a large LCAT-deficient kindred. The activity was absent in the homozygotes and was decreased to 50% of normal in the heterozygotes. Endogenous cholesterol esterification rate measurements did not differentiate the heterozygotes from the unaffected family members or normal subjects. The heterozygotes had significantly higher fasting plasma triglycerides, apo B, and lower HDL-cholesterol and apo AI than the unaffected family members. The HDL of the heterozygotes had the same mass of free cholesterol and triglyceride, but the mass of cholesteryl ester was reduced by 47%. The differences were not related to abnormal postheparin lipolytic activities. However, cholesteryl ester transfer activity in the lipoprotein-free (d greater than 1.21 bottom) fraction of plasma was significantly (P less than .05) decreased in the heterozygotes when compared to unaffected members. We conclude that the low LCAT activity is the likely cause of the qualitative and quantitative differences in the plasma lipoproteins of the heterozygotes in this family with LCAT deficiency. However, the low HDL and apo A-I levels are not associated with either a family or personal history of premature atherosclerosis.
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PMID:Plasma lipoprotein abnormalities in heterozygotes for familial lecithin:cholesterol acyltransferase deficiency. 312 80

The epidemiological associations between the plasma concentrations of several components of high density lipoprotein (HDL) and plasma lecithin:cholesterol acyltransferase (LCAT) concentration have been studied in 101 men aged 52-67 years. Subjects were apparently healthy, and had been selected to provide a wide range of HDL-cholesterol levels. A weak positive correlation was observed between plasma total HDL-cholesterol concentration and LCAT concentration (r = 0.24, P less than 0.02). This reflected an association between HDL3-cholesterol (measured by precipitation) and enzyme concentration (r = 0.21, P less than 0.05). Apoprotein (apo) A-II concentration was also positively correlated with LCAT (r = 0.27, P less than 0.01). HDL2-cholesterol and apo A-I concentration were unrelated to LCAT concentration, as also were the HDL2/HDL3 and HDL-cholesterol/apo A-I ratios. The associations of HDL3 cholesterol and apo A-II with LCAT were strengthened when allowance was made by multiple regression for the effect of log plasma triglyceride; under these circumstances variation in LCAT explained statistically 8% of the variance in HDL3-cholesterol, and 10% of that in apo A-II.
Atherosclerosis 1988 Feb
PMID:Relationship of high density lipoprotein composition to plasma lecithin:cholesterol acyltransferase concentration in men. 312 47

An atherogenic diet (AD) consisting entirely of normal foods for westernized people was fed to female Vervet monkeys for 4 years. The plasma low density lipoprotein (LDL) cholesterol pool was increased and progression of atherosclerosis was enhanced by the AD compared to a more prudent Western diet. The increased LDL-cholesterol was carried by a 3-fold increase in particles of relatively normal composition and not by packing cholesterol esters into the cores of enlarged LDL particles, as has been reported after feeding semisynthetic diets loaded with extra cholesterol. Nevertheless, these LDL particles were atherogenic. The AD changed the fatty acid composition of LDL-cholesterol esters and triacylglycerol, notably by increasing arachidonic and reducing linoleic acid. Multivariate analysis showed that measures and scores of atherosclerosis were significantly dependent on sphingomyelin and phosphatidylcholine in LDL and on arachidonic acid in LDL-triacylglycerol. Although apolipoprotein B, free cholesterol, esterified cholesterol and lysophosphatidylcholine in plasma LDL and atherosclerosis were significantly positively correlated in bivariate analysis they were not selected by multivariate analysis as the strongest determinants of atherogenesis. Cholesterol in plasma high density lipoprotein was not changed by the AD and lecithin:cholesterol acyltransferase activity in plasma was inversely linked to atherosclerosis. Subcutaneous fatty acids reflected dietary fatty acids.
Atherosclerosis 1988 Nov
PMID:Plasma low density lipoprotein composition in relation to atherosclerosis in nutritionally defined Vervet monkeys. 314 48

Thirty postmenopausal women were randomly treated with desogestrel (DG) or levonorgestrel (LN) 125 micrograms/day for 3 weeks. Desogestrel reduced the serum total and free (non-protein bound) testosterone concentrations. It caused a small decrease in the sex hormone binding globulin capacity (SHBG) but did not influence the free testosterone index (testosterone/SHBG ratio). Levonorgestrel, on the other hand, did not influence the free testosterone concentration, but caused a significant increase in the free testosterone index. Levonorgestrel reduced the HDL and particularly the HDL2 cholesterol concentrations (mean change from 1.75 to 1.45 mmol/l for HDL and from 0.73 to 0.50 mmol/l for HDL2, P less than 0.001). It also caused a reduction in the VLDL triglyceride (P less than 0.05) but not the total serum triglyceride concentration. Desogestrel did not cause any significant changes in HDL or HDL2 cholesterol concentrations, but it reduced the VLDL triglyceride (P less than 0.01) and total serum (P less than 0.05) triglyceride concentrations. Neither of the two progestins influenced the postheparin plasma lipoprotein lipase (LPL) activity or the serum cholesterol esterification rate by lecithin:cholesterol acyltransferase (LCAT). It is therefore possible that both steroids decreased the hepatic output of triglycerides, which may be clinically important since both progestins are used in combination with ethinylestradiol (EE) which increases the hepatic TG synthesis. The failure of desogestrel to change HDL levels is consistent with earlier data on the lack of effects on HDL by non-androgenic progestins. Levonorgestrel increased the mean activity of postheparin plasma hepatic lipase (HL) from 23.3 to 28.0 mumol X h-1 X ml-1 (P less than 0.05). In contrast, this activity was not influenced by desogestrel. The magnitude of the changes in postheparin plasma HL activity and the free testosterone index (testosterone/SHBG ratio) showed significant positive correlation (+ 0.41, P less than 0.05). On the other hand, the changes in the HDL2 cholesterol and the postheparin plasma HL activity were inversely interrelated (r = 0.52, P less than 0.01). These relationships are consistent with the idea that the effects of different progestins on the HDL cholesterol are mediated by the sex steroid sensitive hepatic endothelial lipase.
Atherosclerosis 1985 Mar
PMID:Effects of two progestins with different androgenic properties on hepatic endothelial lipase and high density lipoprotein2. 315 21

Effects of prolonged stress on lipid metabolism factors were studied for 9 weeks using four groups of young New Zealand rabbits. Two groups (A,B) were rendered atherosclerotic by administering 1% (w/w) cholesterol. One group (C) was subjected to cold stress together with one of the atherosclerotic groups (B); one group was used as control (N). At the end of treatment serum total cholesterol and total lipids of A and B increased significantly, while in stress group (C) a significant decrease was observed. HDL-C levels were reduced in all experimental groups. Triglycerides did not change in A, while they were reduced in both stress groups (C,B). Serum lecithin:cholesterol acyltransferase (LCAT) activity levels of B and C were decreased. Lipoprotein electrophoresis patterns showed a significant redistribution of percentage values in all experimental groups: %LDL-C increased and %VLDL-C decreased in all groups, %HDL-C declined in A and B and did not change in C. The combination of stress and atherosclerosis in rabbits elicits far greater alterations in lipid and lipoprotein profiles than stress or atherosclerosis alone. A stress and atherosclerotic diet combination may be a hazardous one in relation to CHD and atherosclerosis.
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PMID:Effects of cold stress on serum lipids, lipoproteins, and the activity of lecithin:cholesterol acyltransferase in rabbits. 337 4

The transfer of insoluble cholesteryl esters among lipoprotein particles is a vital step in normal cholesterol homeostasis and may be involved in the development of atherosclerosis. Extrahepatic tissues lack the enzymes required for the degradation of sterols to the excretable form of bile acids. Cholesterol synthesized in these tissues in excess of that needed for the synthesis of cell membranes or steroid hormones must accordingly be returned through the plasma to the liver for catabolism. The series of reactions involved has been termed reverse cholesterol transport. Catalysed steps of this pathway are believed to include an efflux from peripheral cells, which generates a diffusion gradient between these membranes and extracellular fluid; esterification of this cholesterol by lecithin-cholesterol acyltransferase (LCAT) (phosphatidylcholine-sterol acyltransferase) acting on species of high-density lipoproteins; transfer of the cholesteryl esters formed (largely to low- and very low-density lipoproteins) (LDL and VLDL) by a cholesteryl ester transfer protein (CETP); and removal of these lipoproteins, together with their cholesteryl ester content, by the liver through receptor-mediated and nonspecific endocytosis. Of these steps, the CETP reaction is the least characterized. Several laboratories have reported the purification from human plasma of proteins active on cholesteryl ester transfer between lipoprotein particles and possibly between cells and plasma. However, the reported relative molecular mass (Mr), abundance and specificity of the purified activities have differed considerably. We have recently described the preparation of a highly active CETP of Mr 74,000 purified about 100,000-fold from human plasma, which may represent the functional component of earlier preparations. Using a partial amino-acid sequence from this purified protein, CETP complementary DNA derived from human liver DNA has been cloned and sequenced and the cloned DNA used to detect CETP messenger RNA in a number of human tissues.
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PMID:Cloning and sequencing of human cholesteryl ester transfer protein cDNA. 360 Jul 59


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