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: EC:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have measured rates of ketogenesis and malonyl-CoA contents of hepatocytes isolated from meal-fed rats under a variety of incubation conditions in order to determine the relationship between the intracellular malonyl-CoA level and the rate of ketogenesis. Evidence obtained from rat liver homogenates suggested that malonyl-CoA, which is a major determinant of fatty acid synthesis in vivo, also inhibits carnitine acyltransferase I (EC 2.3.1.21) and thereby decreases the rate of ketogenesis (McGarry, J.D., Mannaerts, G.P., and Foster, D.W. (1977) J. Clin. Invest. 60, 265-270). In hepatocytes from meal-fed rats, malonyl-CoA could be increased by glucose or lactate plus pyruvate and decreased by glucagon, oleic acid and the fatty acid synthesis inhibitor 5-(tetradecyloxy)-2-furoic acid. Malonyl-CoA varied from 14.8 +/- 1.2 to 1.4 +/- 0.1 nmol/g wet weight of cells. Rates of ketone body production varied from 0.10 +/- 0.01 to 0.96 +/- 0.06 mumol/min/g wet weight of cells and varied inversely with the malonyl-CoA content. Dixon plots and Cornish-Bowden plots of data suggest that malonyl-CoA is a competitive inhibitor of ketogenesis with a Ki of 2 nmol/g wet weight of cells. We conclude that in hepatocytes from meal-fed rats the cellular content of malonyl-CoA and the concentration of long chain fatty acid available to the cells are major determinants of the rate of ketogenesis.
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PMID:Ketogenesis and malonyl coenzyme A content of isolated rat hepatocytes. 63 84

Mersalyl inhibited the respiration of heart mitochondria under conditions that required the transport of (-)-carnitine and acyl(-)-carnitines. The exchange of external carnitine and acylcarnitines for intramitochondrial carnitine was also inhibited by mersalyl and 1 mM mersalyl proved suitable for the inhibitor-stop assay of carnitine acylcarnitine translocase. The carnitine-carnitine and (-)-carnitine-acetyl(-)-carnitine exchanges involved a mole to mole exchange. The carnitine-carnitine exchange did not require energy. The carnitine acylcarnitine translocase resembles the Pi transport system in inhibition by mersalyl and N-ethylmaleimide and in lack of a cation requirement for activity; yet the two are not identical inasmuch as operation of only the former transport system was inhibited by long chain acyl(+)-carnitines. Additional results render it improbable that the transport of carnitine and acylcarnitines is catalyzed by any other known mitochondrial transport systems. The carnitine acylcarnitine translocase activity is unlikely to be shared by one of the carnitine acyltransferases because the mersalyl inhibition of carnitine palmitoyltransferase and carnitine acetyltransferase was noncompetitivcase. Rapid acetylation of intramitocondrial free (-)-carnitine occurred when acetyl-CoA was generated intramitochondrially but not with exogenous acetyl-CoA. Theese observations substantiate the view (Pande, S. V. (1975) Proc. Natl. Acad. Sci. U.S.A. 72, 883-887) that a system exists in mitochondria for the transport of carnitine and its esters and that the matrix has a pool of carnitine compounds which has access to that carnitine acyltransferase which is localized on the inner side of the inner mitochondrial membrane.
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PMID:Characterization of carnitine acylcarnitine translocase system of heart mitochondria. 97 93

The heart utilizes fatty acids as a substrate in preference to glucose for the production of energy. The rate of fatty acid uptake and oxidation by heart muscle is controlled by the availability of exogenous fatty acids, the rate of acyl translocation across the mitochondrial membrane and the rate of acetyl-CoA oxidation by the citric acid cycle. Carnitine acyl-CoA transferase appears to have an important function in coupling the fatty acid activation and acyl transfer to the oxidative phosphorylation. Activated fatty acids are also utilized for the synthesis of triglycerides and membrane phospholipids in the myocardium. The inhibition of long chain acyl-carnitine transferase I reduces the oxidation of fatty acids and promotes the synthesis of lipids in the myocardium. Accumulation of fatty acids and their metabolites such as long chain acyl-CoA and long chain acyl-carnitine has been associated with cardiac dysfunction and cell damage in both ischemic and diabetic hearts. Alterations in the composition of membrane phospholipids are also considered to change the activities of various membrane bound enzymes and subsequently heart function under different pathophysiological conditions. Chronic diabetes was found to be associated with increased plasma lipids, subcellular defects and cardiac dysfunction. Lowering the plasma lipids or reducing the oxidation of fatty acids by agents such as etomoxir, an inhibitor of palmitoylcarnitine transferase I was found to promote glucose utilization and remodel the subcellular membranous organelles in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Paradoxical role of lipid metabolism in heart function and dysfunction. 148 Jan 51

This study was designed to examine the time-course of response to inhibition of fatty acid (FA) oxidation in rats rendered mildly diabetic with streptozotocin and fed a high fat diet (50% of energy derived from fat). Etomoxir, a specific carnitine palmitoyltransferase (CPT-1) inhibitor, was administered subcutaneously (12.5 mg/kg) to inhibit long chain fatty acid oxidation. Diabetic and non-diabetic control rats were maintained on the high fat diet. Following an overnight fast, glucose, free fatty acid (FFA) and triglyceride (TG) concentrations were determined after three days, one week and four weeks of treatment. The effect of Etomoxir treatment in reducing fasting glucose concentrations was not evident until after one week, while fasting FFA and TG concentrations were already reduced after three days treatment. All of these changes were maintained over the four week period (P less than 0.001), resulting in reduced levels of fasting plasma glucose (17.6 +/- 2.4 vs 22.3 +/- 1.9 mmol/l), fasting plasma TG (0.32 +/- 0.07 vs 0.98 +/- 0.14 mmol/l) and fasting serum FFA (1.52 +/- 0.26 vs 3.51 +/- 0.69 mEq/l). In addition, the improvements in glucose and lipid levels were accompanied by restored rates of growth towards that of non-diabetic control rats. These results suggest that the short term inhibition of FA oxidation improves fasting glucose, FFA and TG concentrations in diabetic rats fed a high fat diet.
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PMID:The longitudinal effect of inhibiting fatty acid oxidation in diabetic rats fed a high fat diet. 152 21

The effects of sodium 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA), a potent inhibitor of carnitine palmitoyltransferase I, on fatty acid oxidation were investigated using fibroblasts from control subjects and from patients with peroxisomal disorders. [1-14C]Palmitate oxidation was inhibited by 8% of the control value when 15 microM POCA was added to the medium. The inhibition by POCA was significantly (P less than 0.05) stronger in fibroblasts from patients with Zellweger syndrome or with neonatal adrenoleukodystrophy, in which peroxisomes and peroxisomal beta-oxidation enzymes were absent. However, the inhibition in fibroblasts from patients with X-linked adrenoleukodystrophy, in which a specific defect of peroxisomal lignoceroyl-CoA synthetase was speculated, was similar to that in the controls. [1-14C]Lignocerate oxidation was not influenced by the addition of POCA, in samples from the controls and from the patients. These results indicate that peroxisomes account for a small but demonstrable proportion of palmitate oxidation, and add new evidence to the concept that lignocerate is oxidized exclusively in the peroxisomes. Our findings also support the hypotheses that the activity of palmitoyl-CoA synthetase and the enzymes of beta-oxidation cycle in peroxisomes are normal in patients with X-linked adrenoleukodystrophy and that a specific defect of lignoceroyl-CoA synthetase is responsible for the accumulation of very long chain fatty acids in these patients.
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PMID:Effects of sodium 2-[5-(4-chlorophenyl)pentyl]-oxirane-2-carboxylate (POCA) on fatty acid oxidation in fibroblasts from patients with peroxisomal diseases. 199 2

In animal cells long chain fatty acids are transferred into the mitochondria for oxidation as acylcarnitines. Carnitine palmitoyltransferase I in the outer membrane, and carnitine translocase plus carnitine palmitoyltransferase II in the inner membrane catalyse the transfer. Carnitine palmitoyltransferase I is inhibited by malonyl-CoA, an intermediate in fatty acid synthesis. In the liver of fasted, diabetic, or thyreotoxic animals this enzyme shows increased activity and less inhibition by malonyl-CoA. Peroxisomes also contain carnitine acyltransferases and a beta-oxidation enzyme system. This system is particularly active in the shortening of very long chain fatty acids. The carnitine acyltransferases of the peroxisomes presumably are active in the transfer of the shortened acyl-CoAs and the acetyl-CoA to the mitochondria for complete oxidation. The carnitine acyltransferases of the mitochondria can catalyse the formation of propionylcarnitine and branched chain acylcarnitines from branched chain amino acids, and methylthiopropionylcarnitine from methionine. Their formation may represent a "security valve" preventing acyl-CoA accumulation in the mitochondria. The liver, which normally releases carnitine for other tissues, releases the branched chain acylcarnitines even more easily. This may be important for the development of secondary carnitine deficiency in some inborn errors of metabolism which are accompanied by the accumulation of acyl-CoAs in the tissue.
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PMID:The role of carnitine in intracellular metabolism. 219 93

The effects of palmitate on mechanical failure of ischemic hearts were studied in acutely (48-hour) and chronically (6-week) streptozotocin diabetic rats. Coronary flow was reduced by 50% in isolated working hearts perfused at a 15 cm H2O preload and 100 mm Hg afterload by the one-way ball valve model of ischemia. Peak systolic pressure (PSP) and cardiac output (CO) decreased 40% by 4 minutes in control hearts perfused with 11 mM glucose and paced at 280 beats/min, compared with 50% in hearts from acutely diabetic rats. Addition of 1.2 mM palmitate to the perfusate accelerated failure rates, with PSP and CO decreasing 65% and 80% by 4 minutes in control and acutely diabetic rat hearts, respectively. In chronically diabetic rats, mechanical function could not be maintained in palmitate-perfused hearts paced at 280 beats/min, even in the absence of ischemia. If these hearts were paced at 250 beats/min and subjected to ischemia, PSP and CO decreased 90% by 4 minutes, regardless of whether palmitate was added to the perfusate. Under these conditions, PSP decreased less than 10% by 4 minutes in both palmitate- or glucose-perfused control hearts. Etomoxir (10(-9) M), a carnitine palmitoyltransferase I inhibitor, markedly decreased the rate of mechanical failure in both acutely and chronically diabetic rat hearts, in the presence and absence of palmitate. The beneficial effect of Etomoxir on mechanical function did not occur as a result of a decrease in either myocardial long chain acyl-coenzyme A or long chain acylcarnitine levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Response of isolated working hearts to fatty acids and carnitine palmitoyltransferase I inhibition during reduction of coronary flow in acutely and chronically diabetic rats. 252 94

Myocardial extraction and the characteristic tissue clearance of radioactivity following bolus injections of a radioiodinated (125I) long chain fatty acid (LCFA) analog 15-p-iodophenylpentadecanoic acid (IPPA) were examined in the isolated perfused working rat heart. Radioactivity remaining in the heart was monitored with external scintillation probes. A compartmental model which included nonesterified tracer, catabolite, and complex lipid compartments successfully fitted tissue time-radioactivity residue curves, and gave a value for the rate of IPPA oxidation 1.8 times that obtained from steady-state release of tritiated water from labeled palmitic acid. The technique was sensitive to the impairment of LCFA oxidation in hearts of animals treated with the carnitine palmitoyltransferase I inhibitor, 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). IPPA or similar modified fatty acids may be better than 11C-labeled physiological fatty acids such as palmitate in this type of study, because efflux of unoxidized tracer and catabolite(s) from the heart are kinetically more distinct, and their contributions to the early data can be reliably separated. This technique may be suitable for extension to in vivo measurements with position tomography and appropriate modified fatty acids.
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PMID:Quantitative analysis of myocardial kinetics of 15-p-[iodine-125] iodophenylpentadecanoic acid. 273 2

The effect of the carnitine palmitoyltransferase 1 (CPT 1) inhibitor, Etomoxir, on glucose oxidation rates was determined in ischemic hearts reperfused in the presence of fatty acids. Isolated working rat hearts were perfused with 11 mM (14C)-glucose and 1.2 mM palmitate at a 15 cm H2O preload, 80 mm Hg afterload. Hearts were subjected to either 60 min aerobic perfusion, or 15 min work followed by 25 min global ischemia then 60 min of aerobic reperfusion. Steady state glucose oxidation rates in reperfused ischemic hearts were not significantly different from non-ischemic hearts. If 10(-9) M Etomoxir was added immediately prior to reperfusion no significant change in glucose oxidation occurred. Addition of 10(-8) M and 10(-6) M Etomoxir, however, significantly increased glucose oxidation. Etomoxir also significantly improved recovery of mechanical function at a concentration of 10(-8) M or greater. As we previously reported, no significant improvement of function was seen when 10(-9) M Etomoxir was added to the perfusate (Lopaschuk GD et al., Circ Res 63: 1036-1043, 1988). Long chain acylcarnitine levels were significantly reduced in the presence of both 10(-9) M and 10(-8) M Etomoxir. These data demonstrate that the beneficial effect of Etomoxir on reperfusion recovery of ischemic hearts is not due to a lowering of long chain acylcarnitine levels. Etomoxir may improve recovery of function by overcoming fatty acid inhibition of glucose oxidation.
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PMID:Glucose oxidation is stimulated in reperfused ischemic hearts with the carnitine palmitoyltransferase 1 inhibitor, Etomoxir. 277 37

The use of 15-p-iodophenyl-beta-methyl-pentadecanoic acid (beta Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioactivity (residue curves) were obtained following bolus injections of both beta Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, beta Me-IPPA kinetics were insensitive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significantly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond beta Me-IPPA-CoA in the oxidative pathway.
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PMID:beta-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart. 235 Nov 85


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