Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Chronic renal failure is associated with hyperlipidemia and atherosclerosis. The mechanism responsible for the observed increase of serum cholesterol in chronic renal disease is not certain. The objective of the present study was to characterize the effect of induced renal failure on 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and cholesterol 7 alpha-hydroxylase, the two rate determining enzymes of the cholesterol and bile acid biosynthetic pathways, respectively. Studies were carried out in rats with subtotal (75%) nephrectomy, which resulted in a marked elevation of blood urea nitrogen (371 +/- 44% of control, P < 0.001), and was accompanied by significant increases in the levels of serum cholesterol (133 +/- 7%, P < 0.005) and triglycerides (185 +/- 25, P < 0.01). In nephrectomized rats, an increase in the specific activity of HMG-CoA reductase (219 +/- 30% above control levels, P < 0.02) was observed. This increase occurred in the presence of elevated hepatic microsomal cholesterol concentrations (150 +/- 13% of controls, P < 0.01). Surprisingly, the increase in HMG-CoA reductase specific activity was not associated with parallel increases in HMG-CoA reductase steady-state mRNA levels and gene transcriptional activity. These uremic rats also exhibited a marked increase in the specific activity of cholesterol 7 alpha-hydroxylase (240 +/- 559% of controls, P < 0.05). There was no concomitant increase in cholesterol 7 alpha-hydroxylase steady-state mRNA levels or gene transcriptional activity. The factors responsible for the observed increases in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase specific activity in renal failure remain to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase in rats with subtotal nephrectomy. 796 47

Excess free radicals are linked to many diseases, including aging, atherosclerosis, and cancer. Previously, we have shown that MA-631 (a complex herbal mixture) inhibits human low-density lipoprotein (LDL) oxidation and may play a role in prevention of atherosclerosis. In this study we further evaluated the in vivo and in vitro antioxidant activity of MA-631. Both the alcoholic and aqueous extracts of MA-631 inhibited enzymatic- and nonenzymatic-induced rat liver microsomal lipid peroxidation in a concentration-dependent manner. The thiobarbituric acid-reactive substances (TBARS) values (nmol malondialdehyde (MDA)/mg microsomal protein) were 1.43 +/- 0.18 for microsomes alone (baseline for enzymatic system), 19.63 +/- 2.50 for microsomes + reduced nicotinamide adenine dinucleotide phosphate (NADPH) (oxidation without inhibitor), 9.89 +/- 1.41 for heated microsomes (baseline for nonenzymatic system), and 27.15 +/- 0.08 for microsomes + ascorbate (oxidation without inhibitor). The concentrations (micrograms/2 ml) of MA-631 which produced 50% inhibition (IC50) of enzymatic- and non-enzymatic-induced lipid peroxidation were 15.2 +/- 2.0 and 17.0 +/- 2.6, respectively, for the aqueous extract, and 4.3 +/- 0.8 and 6.4 +/- 1.2, respectively, for the alcoholic extract. A 2% MA-631 (w:w) supplemented diet fed to rats for three weeks inhibited in vivo, toluene-induced microsomal lipid peroxidation in the brain, kidney, liver, and heart. These results imply that MA-631 may be useful in the prevention of free radical-linked diseases.
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PMID:In vitro and in vivo inhibition of microsomal lipid peroxidation by MA-631. 809 Aug 22

Altered homocysteine metabolism is implicated as a pathogenic factor in atherogenesis, neoplasia, and aging. Hereditary enzymatic deficiencies and nutritional deficiencies of folate, pyridoxine, or cobalamin are associated with elevated blood homocysteine, accelerated atherosclerosis, and manifestations of aging. The failure of malignant cells to metabolize homocysteine thiolactone to sulfate is attributed to deficiency of thioretinaco, a complex containing cobalamin, homocysteine thiolactone, and retinoic acid. The sulfhydryl group of homocysteine is believed to act catalytically with ferric or cupric ions in a mixed function oxidation system to generate hydrogen peroxide, oxygen radicals, and homocysteinyl radicals. These reactive species may interact with the active site of enzyme protein to cause inactivation of catalytic activity. Homocysteine thiolactone is oxidized to sulfate by a process involving ascorbate, thioretinamide, and superoxide, under the control of thyroxine and growth hormone. Thioretinaco is believed to be the active site of adenosine triphosphate (ATP) binding in oxidative phosphorylation with the participation of oxygen, ascorbate, proton gradient, and electron transport. Depletion of thioretinaco from mitochondrial and microsomal membranes may be associated with increased formation and release of radical oxygen species within neoplastic and senescent cells. Specific proposals are made for investigating the importance of homocysteine metabolism in the oxidative modification of proteins and lipids.
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PMID:Homocysteine metabolism and the oxidative modification of proteins and lipids. 832 40

Squalene synthase (SQS) catalyses a step following the final branch in the pathway of cholesterol biosynthesis. Inhibition of this enzyme, therefore, is an approach for the treatment of atherosclerosis with the potential for low side effects. We have characterised the inhibition of rat liver microsomal SQS by 3-(biphenyl-4-yl)quinuclidine (BPQ). BPQ follows slow binding kinetics in that the rate of accumulation of product decreases with time if the inhibitor is added when the assay is started. Preincubation of BPQ and SQS leads to a biphasic dose-response where accumulation of product is linear with time only for the sensitive phase. When the farnesyl pyrophosphate (FPP) substrate is present at 19.6 microM, approximately 77% of the SQS activity is sensitive to the inhibitor (vOs) and the remainder is insensitive (vOi). The apparent inhibition constants (K'i values) are respectively K'is = 4.5 nM and K'ii = 1300 nM. Similar biphasic behaviour is exhibited by other inhibitors and in microsomes prepared from human and marmoset liver. As the concentration of FPP is reduced below 19.6 microM, there is a decrease in the relative contribution from vOi. Conversely, the value of K'is for BPQ remains constant when the FPP concentration is changed, showing noncompetitive kinetics with respect to this substrate. Possible causes of the observed kinetics are discussed. Inhibition by BPQ is said to follow tight binding kinetics because the value of K'is is similar to the concentration of inhibitor binding sites. Thus, to avoid an artefactual variation in potency when the enzyme concentration is varied, it is necessary to allow for the effects of depletion of free inhibitor. Furthermore, estimates of potency that average activity across the two phases are influenced by the relative contributions of each phase. These contributions differ according to the FPP concentration and the species used as the source of microsomes. Thus, it is necessary to separate the phases to compare measurements made in different experiments. Our observations indicate that careful experimental design and data analysis are required to characterise the kinetics of SQS inhibitors.
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PMID:Inhibition of squalene synthase in vitro by 3-(biphenyl-4-yl)-quinuclidine. 863 90

The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systematically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.
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PMID:Acyl-CoA:Cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT. 869 72

In microsomal preparations of CaCo-2 cells pravastatin decreased cholesterol esterifying activity at 25 micrograms/ml to 82.5% and at 800 micrograms/ml to 56.2% of controls. Pravastatin reduced cholesteryl ester formation dose-dependently also in viable CaCo-2 cells. However, the maximal inhibition was by 90.4% at pravastatin concentration of 25 micrograms/ml, half maximal inhibition occurred between concentrations of 5 and 10 micrograms/ml. Addition of mevalonolactone, which serves as endogenous source of cholesterol, antagonized this effect. At 10 mM mevalonolactone (MVL) even doses up to 200 micrograms/ml of pravastatin were ineffective. On the other hand, pravastatin suppressed cholesteryl ester formation when acyl-CoA cholesterol acyltransferase (ACAT) (E.C. 2.3.1.26) activity was stimulated by addition of exogenous liposomal or Low Density Lipoprotein (LDL)-derived cholesterol. This inhibition was refractory to increasing amounts of exogenous cholesterol up to 400 micrograms/ml. Therefore we conclude that only excessive doses of pravastatin suppress ACAT activity directly. In viable cells the observed inhibition of cholesteryl ester formation is due to the block in de novo synthesis of cholesterol, causing a lack of substrate for ACAT and of non-sterol products of mevalonic acid. Furthermore pravastatin interferes with the esterification and/or intracellular transport only of exogenous cholesterol, confirming former results of a compartmentalized cholesterol metabolism in the enterocyte.
Atherosclerosis 1996 Aug 23
PMID:Reduced cholesterol esterification in CaCo-2 cells by indirect action of pravastatin. 883 28

For decades, research interest has focused on hypertriglyceridemia and hypercholesterolemia, because of their association with atherosclerosis. Recently, however, increasing attention has been paid to rare hypolipidemic states that can cause adverse consequences in young patients. Studies of genetic disorders of fat transport have afforded new insights into the mechanisms involved in intestinal lipid handling and lipoprotein metabolism. This article reviews briefly the current state of knowledge about inherited lipoprotein deficiencies, including abetalipoproteinemia, hypobetalipoproteinemia and chylomicron retention disease. These disorders share many common characteristics: they all cause fat malabsorption, low levels of circulating lipids and fat-soluble vitamins, failure to thrive in early childhood, ataxic neuropathy and visual impairment. However, their etiology is genetically different. Abetalipoproteinemia is caused by the absence of microsomal transfer protein, whereas hypobetalipoproteinemia is due to defects in the apolipoprotein B gene. The etiopathogenesis of chylomicron retention disease is as yet unexplained. Research on these rare, inherited fat disorders of absorption will continue to provide significant advances in our understanding of human physiology and may yield novel therapeutic approaches to atherosclerosis.
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PMID:The genetic basis of primary disorders of intestinal fat transport. 888 69

The microsomal enzyme acyl-CoA:cholesterol acyltransferase (ACAT; EC 2.3.1.26) catalyzes the esterification of cellular cholesterol with fatty acids to form cholesterol esters. ACAT activity is found in many tissues, including macrophages, the adrenal glands, and the liver. In macrophages, ACAT is thought to participate in foam cell formation and thereby to contribute to atherosclerotic lesion development. Disruption of the gene for ACAT (Acact) in mice resulted in decreased cholesterol esterification in ACAT-deficient fibroblasts and adrenal membranes, and markedly reduced cholesterol ester levels in adrenal glands and peritoneal macrophages; the latter finding will be useful in testing the role of ACAT and macrophage foam cell formation in atherosclerosis. In contrast, the livers of ACAT-deficient mice contained substantial amounts of cholesterol esters and exhibited no reduction in cholesterol esterification activity. These tissue-specific reductions in cholesterol esterification provide evidence that in mammals this process involves more than one form of esterification enzyme.
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PMID:Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. 894 57

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is the intracellular enzyme responsible for the esterification of cholesterol with long-chain fatty acyl-CoA derivatives and has been implicated in atherosclerosis and gallstone disease. The effects of exogenous cholesterol and dithiothreitol (DTT) on the ACAT activity of human liver microsomes have been determined. Pre-incubation of microsomes with exogenous cholesterol gave a marked stimulation of activity. Experiments with [3H]cholesterol and [14C]oleoyl-CoA indicated the time course of equilibration of exogenous with endogenous cholesterol as ACAT substrates, and showed that ACAT activity could be accurately measured using [3H]cholesterol/Tween 80, providing that the concentration of endogenous microsomal cholesterol was also determined. Pre-incubation of liver microsomes for 90 min in the presence of 2 mmol/l DTT and exogenous cholesterol/Tween 80 resulted in a 60% reduction in ACAT activity, compared with the corresponding activity when DTT was omitted. If microsomes were pre-incubated with DTT prior to the pre-incubation with exogenous cholesterol/Tween 80, an 85-90% reduction in ACAT activity occurred. In contrast, pre-incubation of microsomes with DTT in the absence of exogenous cholesterol/Tween 80 (only endogenous cholesterol present) resulted, initially in a stimulation of ACAT activity; on further pre-incubation, activity returned to control levels. These results indicate that the supply of cholesterol to the enzyme active site is an important factor in ACAT assays in vitro and that DTT has a major effect on this process, suggesting that these factors may be important in controlling ACAT activity in vivo.
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PMID:Effect of exogenous cholesterol and dithiothreitol on the activity of human liver microsomal acyl-coenzyme A:cholesterol acyltransferase (ACAT). 896 Jul 84

Iron overload, with its associated toxic effects, has serious health consequences and results in damage to the liver, heart and other organs. Salicylate may be used as the lipophilic carrier, transporting more iron into hepatocytes. In this study, we examined the effect of the combined administration of these compounds on plasma lipid profile and lipoprotein composition, as well as on hepatic lipid concentration. Male Spraque-Dawley rats were injected i.p. with Fe (15 mg/kg weight). This injection was repeated 24 h later with a gavage of sodium salicylate (700 mg/kg). Control rats received 0.9% NaCl only. The peroxidation indices TBARS (P < 0.001) and conjugated dienes (P < 0.05) significantly increased in the blood (50 and 122%, respectively) and liver (333 and 101%, respectively) of Fe salicylate-treated rats. Concomitantly, blood and liver arachidonic acid content was diminished by iron treatment. In parallel, the plasma lipid profile was markedly affected in Fe-salicylate treated-rats. Lower plasma concentrations of total cholesterol (25%, P < 0.0001) cholesteryl ester, (34%, P < 0.001) and high-density lipoprotein-cholesterol (50%, P < 0.001) were observed. Lipoprotein composition analysis revealed enrichment of free cholesterol and depletion of cholesterol ester in very low-density, intermediate-density, low-density and high-density (HDL2, HDL3) lipoproteins. Furthermore, SDS-polyacrylamide gel electrophoresis revealed several alterations in the apolipoprotein distribution of these lipoproteins. The activity of lecithin:cholesterol acyltransferase was unchanged and could not account for the reduction of cholesterol esterification. As for the plasma, the liver exhibited a significant (P < 0.001) decrease in total cholesterol (2.42 +/- 0.07 versus 1.89 +/- 0.06 mg/g liver), essentially due to a reduction in cholesteryl ester (0.93 +/- 0.07 versus 0.51 +/- 0.03 mg/g, P < 0.001). Again, the activity of ACAT (dpm/mg microsomal protein) was not lower (12,700 +/- 1250) than that of controls (9650 +/- 1080). Thus, the iron-salicylate was able to induce peroxidation and to profoundly affect the intravascular and intrahepatic lipid, and plasma lipoprotein metabolism. Additional work is needed to elucidate the mechanisms involved in the underlying lipid and lipoprotein abnormalities.
Atherosclerosis 1997 Mar 21
PMID:Iron-salicylate complex induces peroxidation, alters hepatic lipid profile and affects plasma lipoprotein composition. 910 57


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