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)

A 15-year-old girl with a large accumulation of lipid in the muscle fibers, was suffering from systemic carnitine deficiency. She died in acidosis. The blood carnitine level was normal. At necropsy, carnitine levels were low in skeletal muscles and heart, whilst a normal level was found in the liver. Carnitine palmitoyltransferase II and palmitoyl-CoA synthetase activities were increased, whereas carnitine acetyltransferase, glycerol-3-phosphate dehydrogenase (FAD) and succinate dehydrogenase were decreased. Investigation of blood and skeletal muscle of the family members revealed marked abnormalities in a 7-year old sister who had only minor neurological symptoms. Histochemical investigation revealed abnormal accumulations of lipid between the myofibrils. Carnitine was decreased in her skeletal muscle and blood. Muscular carnitine palmitoyltransferase II and palmitoyl-CoA synthetase were again increased in activity while glycerol-3-phosphate dehydrogenase (FAD) was decreased. The activities of succinate dehydrogenase, carnitine palmitoyltransferase I and glycerol-3-phosphate dehydrogenase (NAD+) were normal. The unexpected normal carnitine level in blood and liver of the deceased patient was attributed to muscle wasting, which was confirmed by the very high blood level of creatine phosphokinase. This fatal case indicates that the fasting condition must be avoided in persons with carnitine deficiency. In crises, glucose supply is necessary since gluconeogenesis may be blocked.
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PMID:Familial carnitine deficiency. A fatal case and subclinical state in a sister. 15 48

1. Activities of 3-oxo acid CoA-transferase and carnitine palmitoyltransferase together with tri- and di-acylglycerol lipase were present in red and heart muscles of the teleost fish. However, d-3-hydroxybutyrate dehydrogenase activity was not detectable. These results suggest that the heart and red muscles of the teleosts should be able to utilize the fat fuels triacylglycerol, fatty acids or acetoacetate, but not hydroxybutyrate. The muscles from the elasmobranchs differed in that d-3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase activities were present, but carnitine palmitoyltransferase activity was not detectable. This suggests that ketone bodies are the most important fat fuels in elasmobranchs. 2. The concentrations of acetoacetate, 3-hydroxybutyrate, glycerol, non-esterified fatty acids and triacylglycerols were measured in blood or plasma of several species of fish (teleosts and elasmobranchs) in the fed state. Teleosts have a 10-fold higher concentration of plasma non-esterified fatty acids, but a lower blood concentration of ketone bodies; both acetoacetate and 3-hydroxybutyrate are present in blood of elasmobranchs, whereas 3-hydroxybutyrate is absent from that of the teleosts. 3. The effects of starvation (up to 150 days) on the concentrations of blood metabolites were studied in a teleost (bass) and an elasmobranch (dogfish). In the bass there was a 60% decrease in blood glucose after 100 and 150 days starvation. In dogfish there was a large increase in the concentration of ketone bodies, whereas in bass the concentration of acetoacetate (the only ketone body present) remained low (<0.04mm) throughout the period of starvation. The concentration of plasma non-esterified fatty acids increased in bass, but decreased in dogfish. These changes are consistent with the predictions based on the enzyme-activity data. 4. Starvation did not change the activities of ketone-body-utilizing enzymes or that of phosphoenolpyruvate carboxykinase in heart and red skeletal muscles of both fish, but it decreased markedly the activity of phosphoenolpyruvate carboxykinase in white skeletal muscle of both fish. However, in the liver of the dogfish, starvation resulted in a twofold increase in the activities of 3-hydroxybutyrate dehydrogenase and acetoacetyl-CoA thiolase, whereas in bass liver it decreased the activity of acetoacetyl-CoA thiolase and increased that of 3-oxo acid CoA-transferase. The activity of phosphoenolpyruvate carboxykinase was increased twofold in the liver of bass, but was unchanged in that of the dogfish. 5. The difference in changes in concentrations of blood metabolites and enzyme activities in the two fish support the suggestion that, in starvation, ketone bodies, but not non-esterified fatty acids, are an important fuel for muscle in elasmobranchs, whereas non-esterified fatty acids, but not ketone bodies, are an important fuel in teleosts. The results are discussed in relation to the evolution of a discrete lipid-storing adipose tissue in teleosts and higher vertebrates.
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PMID:Activities of enzymes of fat and ketone-body metabolism and effects of starvation on blood concentrations of glucose and fat fuels in teleost and elasmobranch fish. 53 30

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

The main hormones involved in ketone-body metabolism are the anabolic hormone insulin and the primarily catabolic hormones, glucagon, cortisol, catecholamines and growth hormone. These hormones may regulate ketone-body metabolism at three sites: adipose tissue, by regulating fatty acid supply to the liver; the liver itself, by determining the relative activities of the re-esterification and fatty acid oxidation pathways; and the periphery, by influencing the rate of extrahepatic utilization of ketone bodies. The first two are quantitatively the most important. Insulin acts on all three regulatory sites. In adipose tissue lipolysis is inhibited and re-esterification enhanced with consequent decrease of fatty acid release. Both these processes are extremely insulin-sensitive. In the liver insulin increases fatty acid synthesis and esterification. At the same time malonyl-CoA formation is increased, which inhibits the acylcarnitine transferase system and thus decreases the transport of fatty acids into mitochondria and hence fatty acid oxidation and ketogenesis. Insulin also has a small stimulatory effect on extrahepatic ketone-body utilization. The effects of glucagon depend on whether insulin is present. In normal man glucagon stimulates insulin secretion and the predominant effect is that of insulin, i.e. decreased ketogenesis. In insulin deficiency glucagon has a mild stimulatory effect on lipolysis, increasing fatty acid supply to the liver. The main effects of glucagon are, however, on the liver. It activates the carnitine acyltransferase system through inhibition of malonyl-CoA synthesis. Fatty acid oxidation is increased and ketogenesis enhanced. The overall effect on the liver depends on the relative amounts of insulin and glucagon present. Studies with somatostatin show that glucagon can increase ketogenesis acutely when insulin secretion is inhibited in normal man, but the effects are short-lived. Cortisol has similar effects to glucagon. In the presence of insulin there is a small increase in fatty acid mobilization from adipose tissue, secondary to impaired glucose entry, and perhaps a small effect on lipolysis itself. This fatty acid is, however, directed to triacylglycerol in the liver. In insulin deficiency, again demonstrated by somatostatin infusion, the incoming fatty acidstone-body formation. The mechanism remains obscure. Catecholamines, in contrast, have their most potent effects on adipose tissue, stimulating lipolysis and fatty acid release even in the presence of insulin. They thus act mainly by enhancing precursor supply and have only minor effects on liver and no effect on peripheral utilization. Growth hormone, like glucagon, has little effect in the presence of insulin, but can enhance ketogenesis in insulin deficiency, although again the mechanism is unknown. Thus in normally fed man the effects of insulin will be overriding and little ketogenesis occurs because of limited fatty acid availability in the liver...
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PMID:Hormonal regulation of ketone-body metabolism in man. 74 14

The regulation of acetyl-CoA carboxylase (ACC) by glucose and other fuel molecules has been examined in Fao Reuber hepatoma cells and Syrian hamster insulin tumor (HIT) cells in order to determine whether lipogenic substrates acutely alter ACC activity and to examine the mechanism of such regulation. In Fao cells, preincubated in simple medium without substrates, glucose addition results in a rapid activation of ACC. This effect, mimicked by other fuels such as lactate, is characterized by an increase in enzyme Vmax and a decrease in the activation constant for citrate. Several lines of evidence indicate that this activation of ACC is due to enzyme dephosphorylation, including the kinetic changes observed, the persistence of enzyme activation through ACC isolation, the necessity of inclusion of sodium fluoride/EDTA in the cell lysis buffer for preservation of the glucose-induced change, and the direct demonstration of diminished 32P-labeling of ACC after glucose exposure. Identical effects of glucose are also observed in HIT cells, although the ACC activation is smaller in magnitude and less sensitive than that observed in Fao cells. Other insulin secretagogues such as glutamine, lactate, and isobutylmethylxanthine are also found to activate HIT ACC. Others have suggested that glucose-induced changes in malonyl-CoA in beta-cells may be linked to glucose-induced insulin secretion. However, studies conducted in late passage HIT cells, which fail to secrete insulin in response to glucose stimulation, reveal the same glucose-induced activation seen in early passages, secretion-competent HIT cells, suggesting that glucose-induced ACC activation is not by itself sufficient to provoke insulin secretion. Taken together, these findings indicate that glucose and other fuel molecules can play a major role in the rapid regulation of the fatty acid synthesis pathway. The activation of fatty acid synthesis by substrate-induced ACC dephosphorylation insures ultimate fuel storage of glucose-derived carbon as fatty acid, while substrate-induced increases in the ACC product, malonyl CoA, would serve to simultaneously limit the rate of fatty acid oxidation through its allosteric regulation of carnitine palmitoyltransferase I.
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PMID:Glucose regulation of acetyl-CoA carboxylase in hepatoma and islet cells. 134 95

The interaction of gluconeogenesis and fatty acid oxidation in isolated sheep hepatocytes was studied. Addition of tetradecylglycidic acid, an inhibitor of carnitine palmitoyltransferase I (EC 2.3.1.21), to isolated hepatocytes inhibited gluconeogenesis from a mixture of pyruvate plus lactate and from propionate alone. Inhibition constants for tetradecylglycidic acid on gluconeogenesis were 4.77 +/- 1.00 microM and 7.25 +/- 1.52 microM, respectively, for pyruvate plus lactate and for propionate as gluconeogenic substrates. The inhibition constants were not different. At the highest substrate concentrations examined, gluconeogenesis from pyruvate plus lactate and from propionate in the presence of 10 microM tetradecylglycidic acid was 47.3 and 41.4% of their respective controls. Similar to previous observations with butyrate, caproate addition inhibited gluconeogenesis from propionate by isolated hepatocytes and was unable to prevent inhibition of gluconeogenesis induced by tetradecylglycidic acid. Carnitine palmitoyltransferase I activity was lower in mitochondria isolated from hepatocytes preincubated with insulin than in control hepatocytes. The data suggest 1) that maximum rates of gluconeogenesis in isolated sheep hepatocytes from either pyruvate plus lactate or from propionate as gluconeogenic substrates require beta-oxidation, 2) that intermediates common to the metabolism of butyrate and caproate may be involved in the inhibition of propionate conversion to glucose by isolated sheep hepatocytes, and 3) that carnitine palmitoyltransferase I activity in isolated sheep hepatocytes can be modulated by insulin treatment.
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PMID:Interactions between gluconeogenesis and fatty acid oxidation in isolated sheep hepatocytes. 140 66

The aim of the investigation was to assess whether endogenous triacylglycerol contributes to the maintenance of the contractile and pacemaker activities of the isolated atria from fed and fasted rats. To attain this information, the atria were treated with methylpalmoxirate which is a potent inhibitor of carnitine palmitoyltransferase I. In the presence of glucose, methylpalmoxirate abolished the lipolysis without affecting peak developed tension or the atrial rate. When exposed to a substrate-free medium containing 2-deoxyglucose, the atria displayed a progressive fall of the pacemaker frequency, a pronounced decay of contractile strength and the appearance of contracture. These derangements appeared faster in the atria from fed rats coinciding with a smaller triacylglycerol mobilization. Methylpalmoxirate suppressed triacylglycerol breakdown, increased the contracture strength, accelerated the fall of the atrial rate and in a significant number of fasted atria it led to a complete cessation of the spontaneous contractions. The decline of the peak tension was not altered by the inhibitor, probably because the contractile strength was too weak in the glucose-free medium, so that additional negative inotropic effects were not detectable. These data suggest that exogenous glucose in addition to that derived from glycogen meet the atrial energy requirements when the fatty acid oxidation is hindered. The deleterious effects exerted by methylpalmoxirate after the glucose metabolism was eliminated indicate that endogenous triacylglycerol supports, at least partly, the atrial functions.
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PMID:Effects of methylpalmoxirate on isolated rat atria. 143 78

In order to examine the role of fructose 2,6-bisphosphate (Fru-2,6-P2) in non-esterified-fatty-acid-stimulated gluconeogenesis, Fru-2,6-P2 levels were measured in cultured rat hepatocytes under conditions mimicking the fasted state. After addition of either 1.5 mM-palmitate or 10 nM-glucagon, [U-14C]lactate incorporation into glucose increased 2-fold, but only glucagon suppressed Fru-2,6-P2. Prevention of palmitate oxidation with a carnitine palmitoyltransferase-I inhibitor (2-bromopalmitate) diminished glucose production and Fru-2,6-P2 levels. Addition of exogenous glucose to the media increased Fru-2,6-P2 in a dose-related manner, which was further augmented by addition of palmitate. When Fru-2,6-P2 levels were examined in cells cultured under conditions mimicking the fed state (significantly higher basal Fru-2,6-P2 levels and lower glucose production), palmitate oxidation was associated with a significant fall in Fru-2,6-P2. In conclusion, the present studies have demonstrated a dissociation between fatty-acid-stimulated gluconeogenesis and changes in Fru-2,6-P2 in cultured rat hepatocytes. Further experiments suggest that the accumulation of intracellular hexose 6-phosphate as a result of fatty-acid-stimulated gluconeogenesis masks a putative inhibitory effect of fatty acids on Fru-2,6-P2 concentrations.
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PMID:Evidence for dissociation of gluconeogenesis stimulated by non-esterified fatty acids and changes in fructose 2,6-bisphosphate in cultured rat hepatocytes. 144 59

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


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