Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ro 16-0521 is a newly synthesized benzodiazepine derivative which is devoid of reactivity with the brain benzodiazepine receptor. The effects of this drug on plasma lipids and lipoproteins and hepatic cholesterol metabolism have been examined in the cholesterol-fed rat. Drug therapy was associated with dose-related falls in plasma cholesterol concentration, liver cholesterol content, and the activity of the liver enzyme Acyl-CoA cholesterol acyltransferase. Drug therapy abolished the lipid and lipoprotein changes induced by cholesterol feeding, including those associated with a diet supplemented with olive oil to facilitate cholesterol loading. Drug therapy was also associated with an increased activity of the enzyme HMG-CoA reductase and reduced hepatic microsomal cholesterol content. It is suggested that the cholesterol-fed rat will be a suitable model for further mechanistic studies.
Atherosclerosis 1986 Jun
PMID:Effects of Ro 16-0521 on cholesterol metabolism in the rat. 373 45

Inhibitors of the enzyme Acyl-CoA: Cholesterol Acyltransferase are regarded as potentially useful agents in the treatment of hypercholesterolemia and atherosclerosis. We report here a novel series of 2, 6-disubstituted-3-imidazolylbenzopyrane derivatives with significant in vitro ACAT inhibitory activity (IC50 range 0.05-0.5 microM). Compounds of this series such as 26 are examples of a new, structurally distinct class of potent ACAT inhibitors with high specificity for the aortic subtype of the enzyme. The structure-activity relationships of the 3-imidazolylbenzopyrane ACAT inhibitors were investigated by systematic manipulation of two regions of the parent compound 1 and the inhibitory activity resulted linked to the substituent in position 6 of the benzopyrane ring and modulated by the size of lipophilic substituents in position 2. Investigation of the mechanism of the inhibitory effect leads to the conclusion that these compounds act in a non-competitive fashion.
 ...
PMID:Imidazolylbenzopyrane derivatives: a new class of acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors. 753 85

Control of apolipoprotein B (apo B) secretion in hepatocytes occurs partly at the post-translational level. The key step in this process appears to be intracellular degradation of newly synthesized apo B. The aim of this paper was to investigate the mechanisms that regulate apo B secretion by Hep G2 cells, in response to the inhibition of Acyl-CoA Acyltransferase (ACAT) by the compound Sandoz 58035 (S-58035). S-58035 (20 microM) reduced cholesteryl ester synthesis from [14C]oleate by 95%, and increased significantly, in a dose-dependent manner, (2-100 microM) apo B secretion, either in control conditions (from 78 +/- 4.3 to 126 +/- 6.1 ng apo B-100/mg cell protein/4 h) or upon stimulation of apo B secretion by oleate (from 134 +/- 4.23 to 177 +/- 4.3 ng apo B/mg cell protein/4 h). This increased secretion of newly synthesized apo B-100 was confirmed by pulse experiments and by gradient ultracentrifugation of the media. Moreover pulse-chase experiments showed that the addition of S-58035 reduced intracellular degradation of apo B-100, both in control conditions and in the presence of oleate. S-58035 (20 microM) did not affect total cellular cholesterol content, but free cholesterol increased with a concomitant decrease of cholesteryl ester (-20%). S-58035 increased cellular triglyceride mass, which was observed in basal conditions (from 12.8 +/- 1.09 to 22.7 +/- 2.7 micrograms TG/mg cellular protein) and also in presence of oleate (from 48 +/- 0.53 to 59 +/- 6.3 micrograms TG/mg cellular protein). This effect is due to a stimulation of triglyceride synthesis, as determined by incorporation of [3H]glycerol into cellular triglycerides. From these data we conclude that, under our experimental conditions, triglyceride synthesis and/or availability is likely to control intracellular degradation of apo B.
Atherosclerosis 1997 Apr
PMID:Decreased intracellular degradation and increased secretion of apo B-100 in Hep G2 cells after inhibition of cholesteryl ester synthesis. 912 58

Acyl-CoA:cholesterol acyltransferase (ACAT) plays important roles in cellular cholesterol homeostasis and is involved in atherosclerosis. ACAT-1 protein is located mainly in the ER. The hydropathy plot suggests that ACAT-1 protein contains multiple transmembrane segments. We inserted either the hemagglutinin tag or the HisT7 tag at various hydrophilic regions within the human ACAT-1 protein and used immunofluorescence microscopy to determine the topography of the tagged proteins expressed in mutant Chinese hamster ovary cells lacking endogenous ACAT. All of the tagged proteins are located mainly in the ER and retain full or partial enzyme activities. None of the tagged proteins produces detectable intracellular degradation intermediates. Treating cells with digitonin at 5 micrograms/ml permeabilizes the plasma membranes while leaving the ER membranes sealed; in contrast, treating cells with 0.25% Triton X-100 or with cold methanol permeabilizes both the plasma membranes and the ER membranes. After appropriate permeabilization, double immunostaining using antibodies against the N-terminal region and against the inserted tag were used to visualize various regions of the tagged protein. The results show that human ACAT-1 in the ER contains seven transmembrane domains.
 ...
PMID:Human acyl-CoA:cholesterol acyltransferase-1 in the endoplasmic reticulum contains seven transmembrane domains. 1043 3

Acyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme in cellular cholesterol homeostasis and in atherosclerosis. ACAT-1 may function as an allosteric enzyme. We took a multifaceted approach to investigate the subunit composition of ACAT-1. When ACAT-1 with two different tags were co-expressed in the same Chinese hamster ovary cells, antibody specific to one tag caused co-immunoprecipitation of both types of ACAT-1 proteins. Radioimmunoprecipitations of cells expressing the untagged ACAT-1 or the 6-histidine-tagged ACAT-1 yielded a single radiolabeled band of predicted size on SDS-polyacrylamide gel electrophoresis. These results show that ACAT-1 exists as homo-oligomers in intact Chinese hamster ovary cells. We solubilized HisACAT-1 with the detergent deoxycholate or CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonic acid), performed gel filtration chromatography and sucrose density gradient centrifugations in H(2)O and D(2)O, and determined the Stokes radii and sedimentation coefficients of the HisACAT1-detergent complexes. The estimated molecular mass of HisACAT-1 is 263 kDa, which is 4 times that of the HisACAT-1 monomer (69 kDa). Finally, cross-linking experiments in intact cells and in vitro show that the increase in cross-linker concentrations causes an increase in size of the HisACAT-1-positive signals, forming material(s) 4 times the size of the monomer, supporting the conclusion that ACAT-1 is a homotetrameric enzyme.
 ...
PMID:Human acyl-CoA:cholesterol acyltransferase-1 is a homotetrameric enzyme in intact cells and in vitro. 1059 97

Mammalian sterol regulatory enzymes are integral membrane proteins of the endoplasmic reticulum. They play a critical role in liver cholesterol homeostasis and the maintenance of overall cholesterol balance in different species. Because lipid peroxidation has been implicated in hepatic dysfunction and atherosclerosis, we hypothesized that its occurrence could alter the composition and properties of the bilayer lipid environment, and thereby affect the functions of these membrane proteins. Preincubation of rat liver microsomes with iron (Fe)/ascorbate (50 microM/200 microM), known to induce peroxidation, resulted in a significant inhibition of (i) the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase (46%, p < .01), (ii) the crucial enzyme controlling the conversion of cholesterol in bile acids, cholesterol 7alpha-hydroxylase (48%, p < .001), and (iii) the central enzyme for cholesterol esterification: Acyl-CoA:cholesterol acyltransferase (ACAT, 80%, p < .0001). The disturbances of these key enzymes took place concomitantly with the high production of malondialdehyde (350%, p < .007) and the loss of polyunsaturated fatty acids (36.19 +/- 1.06% vs. 44.24 +/- 0.41 in controls, p < .0008). While alpha-tocopherol simultaneously neutralized lipid peroxidation, preserved microsomal fatty acid status, and restored ACAT activity, it was not effective in preventing Fe/ascorbate-induced inactivation of both HMG-CoA reductase (44%, p < .01) and cholesterol 7alpha-hydroxylase (71%, p < .0001). These results indicate that Fe/ascorbate alters the activity of the rate-determining steps in liver cholesterol metabolism, either directly or via lipid peroxidation, capable of modifying their membrane environment. The present data also suggest that the three regulatory enzymes respond differently when exposed to Fe/ascorbate or antioxidants, which may be due to dissimilar mechanisms.
 ...
PMID:Modulation of endoplasmic reticulum-bound cholesterol regulatory enzymes by iron/ascorbate-mediated lipid peroxidation. 1065 90

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular cholesterol. To investigate the role of ACAT-1 in atherosclerosis, we have generated ACAT-1 null (ACAT-1-/-) mice. ACAT activities were present in the liver and intestine but were completely absent in adrenal, testes, ovaries, and peritoneal macrophages in our ACAT-1-/- mice. The ACAT-1-/- mice had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities. This phenotype is similar to dry eye syndrome in humans. To determine the role of ACAT-1 in atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein (apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous xanthomatosis with loss of hair in both ACAT-1-/-:apo E-/- and ACAT-1-/-:LDLR-/- mice. Free cholesterol content was significantly increased in their skin. Aortic fatty streak lesion size as well as cholesteryl ester content were moderately reduced in both double mutant mice compared with their respective controls. These results indicate that the local inhibition of ACAT activity in tissue macrophages is protective against cholesteryl ester accumulation but causes cutaneous xanthomatosis in mice that lack apo E or LDLR.
 ...
PMID:Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. 1077 3

Acyl-CoA:cholesterol acyltransferase (ACAT) is thought to contribute significantly to lipid deposition in macrophages, which subsequently leads to the initiation and progression of atherosclerosis. The aim of the present study was to examine the influence of hypercholesterolemia on arterial hyperplasia induced by endothelial denudation and the direct effect of ACAT inhibition on lesion formation. Rabbits were fed either a cholesterol diet or a regular diet for 4 weeks, and then the left common carotid arteries were denuded of endothelium. After the operation, all rabbits were kept on the regular diet for 2;-6 weeks. Two weeks after the denudation, the degree of intimal thickening and the number of proliferating cells (which were immunohistologically identified to be smooth muscle cells) were similar in hypercholesterolemic and normolipidemic rabbits. After that, both parameters progressively increased in hypercholesterolemic rabbits but declined in normolipidemic rabbits. Macrophages were apparent in the lesions only in hypercholesterolemic rabbits. Next, the effect of the ACAT inhibitor, (1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido] cyclohexane-1-yl 3-[(4R)-N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate (F-1394), on neointimal formation in hypercholesterolemic rabbits was examined. Oral administration of F-1394 significantly reduced neointimal thickening and the extent of macrophages in lesions without affecting serum cholesterol levels. These results suggest that hypercholesterolemia causes macrophage-derived foam cell accumulation in lesions, and that the progression of lesions is accelerated by the presence of macrophages. Moreover, the study shows that F-1394 prevents neointimal formation even in the presence of hypercholesterolemia, indicating that F-1394 may be useful for treating restenosis after percutaneous translumenal coronary angioplasty in hyperlipidemic patients.
 ...
PMID:ACAT inhibitor F-1394 prevents intimal hyperplasia induced by balloon injury in rabbits. 1129 Aug 19

Our full understanding of atherosclerosis and our ability to prevent its sequellae are incomplete. As a result, further investigation of novel antiatherosclerotic mechanisms and agents continues. Acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibition has been evaluated as a potential mechanism by which the current treatment arsenal may be expanded. ACAT is present in a variety of tissues and is responsible for catalyzing the conversion of free cholesterol to the more readily stored cholesteryl esters. Impressive lipid effects demonstrated in animals have not generally been demonstrated in human clinical trials. Partial ACAT inhibition with specific agents has resulted in lesion regression and decreased progression, whereas complete ACAT inhibition via genetic alterations has led to an exacerbation of cholesterol deposition in tissues in animal models. No ACAT inhibitor has yet been fully evaluated in human clinical trials for its impact on atherosclerotic disease progression. Several hurdles, such as sample size requirements needed to detect effect over background therapy and lack of sensitive surrogate efficacy markers, have served as a deterrent to the development of this class of investigational drug. However, with recent technologic advancements, more sensitive methods of measuring disease progression may be available. Human clinical trials are currently underway, with several agents reported in Phase II clinical trials. Within the next few years, results from these trials may determine whether or not ACAT inhibitors will be added to the list of treatment options for the prevention of atherosclerotic disease progression.
 ...
PMID:Inhibition of acyl coenzyme A-cholesterol acyltransferase: a possible treatment of atherosclerosis? 1177 25

Acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors have been shown to reduce atherosclerotic lesions in animals; however, the mechanism(s) for this effect remains unclear. Therefore, we used cultured primary human monocyte-derived macrophages (HMMs) to examine the effect of the ACAT inhibitor, avasimibe (CI-1011), during foam cell formation and during cholesterol efflux from established foam cells. To examine the effect of CI-1011 on foam cell development, HMMs were incubated with aggregated acetylated LDL (ag-acLDL)+/-CI-1011 for 48 h. Total cholesterol (TC) was 29% lower in HMMs incubated with ag-acLDL and CI-1011 compared with ag-acLDL (P<0.05). To determine if TC reduction was due to reduced ag-acLDL uptake by CI-1011, 125I-acLDL binding at 4 degrees C for 4 h to HMMs preincubated with acLDL or ag-acLDL, CI-1011, acLDL+CI-1011, or ag-acLDL+CI-1011 for 48 h was measured. Specific binding was 40% lower in cells preincubated with acLDL+CI-1011, 52% lower in cells preincubated with ag-acLDL+CI-1011 and 49% lower in cells preincubated with CI-1011 compared with cells preincubated with acLDL (P<0.0003). Because CI-1011 appeared to directly affect acLDL binding, 125I-acLDL (3-80 microg protein/ml) binding was done in HMMs preincubated with CI-1011 (0-10 microg/ml) for 48 h. The calculated B(max) decreased in HMMs exposed to increasing concentrations of CI-1011, suggesting that CI-1011 altered scavenger receptor function and/or number. To examine the effects of CI-1011 on cholesterol efflux from established foam cells, we first examined whether CI-1011 was cytotoxic. HMMs were preincubated with ag-acLDL for 24 h, and then radiolabeled with [14C]adenine for 2 h (time zero). The radiolabeled cells were exposed to control RPMI medium or the same medium+HDL, CI-1011, or HDL+CI-1011 for 24 h. The release of [14C]adenine into the medium was not significantly different between cells exposed to RPMI, HDL, CI-1011, or HDL+CI-1011, suggesting that CI-1011 was not cytotoxic. Foam cells exposed to RPMI and CI-1011 (1-10 microg/ml) for 48 h showed time dependent reduction in cellular TC mass, with a corresponding increase in radiolabeled unesterified cholesterol into the medium. We then asked whether CI-1011 enhanced apoE mediated cholesterol efflux. Although cellular apoE increased between 2- and 7-fold in foam cells compared to control macrophages, apoE secreted into the medium was not significantly different between cells exposed to RPMI or CI-1011. Thus, CI-1011 exerted anti-atherogenic effects by reducing TC accumulation, inhibiting acLDL binding, and by limiting lipid storage in HMMs.
Atherosclerosis 2002 Mar
PMID:Anti-atherogenic effects of the acyl-CoA:cholesterol acyltransferase inhibitor, avasimibe (CI-1011), in cultured primary human macrophages. 1188 16


1 2 3 Next >>