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 identified two partially overlapping genomic clones that contain part of the 5' regulatory region of the human carnitine palmitoyltransferase II gene. The 1.2 kb region upstream the transcription start site, as defined by primer extension experiments, shows promoter activity when inserted upstream of a reporter gene and contains a putative insulin responsive element.
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PMID:Identification of 5' regulatory regions of the human carnitine palmitoyltransferase II gene. 808 71

1. Viable myocytes were obtained from rat hearts. Oxidation of [1-14C]palmitate by these cells could be decreased by the addition of glucose (5 mM) or lactate (2 mM). In the presence of glucose, insulin decreased and adrenaline increased palmitate oxidation. 2. The myocytes contained activities of ATP citrate-lyase, acetyl-CoA carboxylase and the condensing enzyme of the fatty acid elongation system. No fatty acid synthase activity was demonstrable in myocytes. 3. In rat hearts perfused with 5 mM glucose, malonyl-CoA content was acutely raised by insulin. In the presence of glucose+insulin, perfusion with palmitate or adrenaline decreased the malonyl-CoA content. 4. It is concluded that malonyl-CoA can be synthesized within cardiac myocytes and that the level of this metabolite can be acutely regulated. This is likely to have consequences for the regulation of carnitine palmitoyltransferase in the heart.
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PMID:Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation. 821 40

It has been proposed previously that the sustained activation of mitogen-activated protein kinase may be necessary for the differentiation of PC12 cells. Differentiation of PC12 cells is induced by many extracellular agonists including nerve growth factor (NGF) and cyclicAMP analogues, but not epidermal growth factor (EGF), insulin or phorbol esters. Our results demonstrate that: (i) 8-(4-chlorophenylthio)-cyclicAMP (CPT-cAMP) activates MAP kinase; this raises the possibility that the MAP kinase pathway may be activated by agents that act through adenylate cyclase; (ii) NGF and CPT-cAMP as well as phorbol esters promote sustained activation of MAP kinase. This suggests that while sustained MAP kinase activation may be associated with differentiation it may not be sufficient, and that other as yet unidentified parallel pathways may be involved.
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PMID:Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen-activated protein kinase. Comparison with the effects of insulin, growth factors and phorbol esters. 830 83

This study was designed to determine the effects of glucose and insulin on malonyl-CoA, the potent inhibitor of carnitine palmitoyltransferase I, in the gastrocnemius/plantaris muscle group. Isolated rat hindlimbs were perfused with Krebs-Henseleit bicarbonate buffer containing fresh erythrocytes (hematocrit = 41) and albumin in a flow-through mode for 60 min. Two experiments were performed. In the first, hindlimbs were perfused with medium containing no glucose and no insulin (n = 9) or with medium containing 10 mM glucose and 100 microU/ml of insulin (n = 9). Gastrocnemius/plantaris malonyl-CoA was 0.6 +/- 0.1 nmol/g in the absence of glucose and insulin vs. 1.4 +/- 0.1 nmol/g when both glucose and insulin were added. In the second experiment, hindlimbs were perfused with medium containing 10 mM glucose alone, 200 microU insulin alone, or with a combination of 10 mM glucose and 200 microU/ml of insulin (n = 8 for each). Malonyl-CoA was decreased in gastrocnemius/plantaris perfused with glucose alone (0.7 +/- 0.2 nmol/g) and with insulin alone (0.7 +/- 0.1 nmol/g) compared with hindlimbs perfused with the combination of glucose and insulin (1.4 +/- 0.2 nmol/g). We conclude that both glucose and insulin are required for preventing a decline in muscle malonyl-CoA.
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PMID:Control of malonyl-CoA by glucose and insulin in perfused skeletal muscle. 833 89

The purpose of these studies was to quantify several mRNAs expressed specifically in pancreatic islet cells and known or postulated to be important for insulin release after acute well defined alterations in levels of plasma glucose. Glucose levels were maintained at 50, 120, or 180 mg/dl (2.8, 6.7, or 10 mM) for 3 h in conscious unrestrained rats. Hypoglycemia (for 3 h) caused significant decreases in pancreatic content of mRNAs for insulin 2 and GLUT-2 to 55 and 34% of control values, respectively. There were no significant changes in insulin 1, amylin, glucokinase, or glucagon mRNAs. Unprocessed insulin 1 and 2 mRNA precursors were decreased to 17 and 10% of levels in controls, consistent with effects of short-term hypoglycemia on new mRNA synthesis. Hyperglycemia (for 3 h) caused no increase in pancreatic content of any mRNA measured. To discriminate between effects of hypoglycemia and hyperinsulinemia in the hypoglycemic animals, rats were made hypoglycemic by infusion with etomoxir, a carnitine palmitoyltransferase I inhibitor that lowers glucose in the fasted (glycogen-depleted) state by inhibiting hepatic gluconeogenesis. A single dose of this agent caused a decrease in glucose from 120 mg/dl (6.7 mM) to 80 mg/dl (4.4 mM) and significantly decreased insulin mRNA and pre-mRNA. These results are consistent with the hypothesis that glucose modulates islet cell gene transcription directly. They indicate that the range of glucose concentrations that modulate gene transcription differs from the levels of glucose that alter both insulin biosynthetic and secretion rates.
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PMID:Hypoglycemia but not hyperglycemia induces rapid changes in pancreatic beta-cell gene transcription. 836 95

To examine the influence of elevated free fatty acid (FFA) levels on hepatic glucose production (HGP) and oxidative and nonoxidative pathways of glucose metabolism, 12 healthy subjects participated in two euglycemic insulin-clamp studies performed with and without infusion of Intralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measurement of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid plus heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhibited by insulin. Suppression of HGP by insulin was impaired by elevated plasma FFA levels. Furthermore, the increase in plasma FFA was associated with a 20% reduction in total glucose metabolism (P < 0.01), which was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by insulin, elevation of plasma FFA had no influence on this key enzyme of glycogen synthesis. In addition, the activities of PDH and CPT were uninfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose-fatty acid cycle under the current conditions. Taken together, the data indicate that the interaction between FFA and glucose metabolism also involves impaired suppression of HGP by insulin.
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PMID:Contribution of muscle and liver to glucose-fatty acid cycle in humans. 847 39

In order to investigate the long-chain fatty acid oxidative capacity of tumour cells, carnitine palmitoyltransferase I (CPT I) and CPT II were selected for study because they are rate-limiting regulatory enzymes. Measurable activities of both CPT I and CPT II were detected in several human and rat tumour cell types and in mouse fibroblasts. The activities were comparable with those previously reported for rat liver CPT I and II, ranging from 1-3 nmoles/min/mg protein for both CPT I and II. Walker 256 tumour tissue also contained detectable CPT I and II activities, thereby demonstrating that tumour tissue in vivo also has the capacity for the processing of fatty acyl CoA's in the mitochondrion. The possible regulation of tumour CPT I and II was investigated using the hormone insulin, both in vitro and in vivo. Insulin was found to increase CPT II activity in the T24/83 human bladder tumour in vitro and in the Walker 256 rat tumour in vivo. The results suggest that insulin may exert some control over the activity of CPT II in certain types of tumour. In contrast, insulin was without effect on CPT I activity in any of the tumours studied, either in vitro or in vivo.
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PMID:Human and rat tumour cells possess mitochondrial carnitine palmitoyltransferase I and II: effects of insulin. 858 32

We studied the effects of fatty acid oxidation on insulin secretion of db/db mice and underlying molecular mechanisms of these effects. At 2-3 months of age, db/db mice were markedly obese, hyperglycemic, and hyperinsulinemic. Serum free fatty acid (FFA) levels were increased in 2-month-old (1.5 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05) and 3-month-old (1.9 +/- 0.1 vs. 1.2 +/- 0.1 mmol/l, P < 0.01) mice compared with the age and sex-matched db/+ mice serving as controls. Glucose-induced insulin release from db/db islets was markedly decreased compared with that from db/+ islets and was specifically ameliorated (by 54% in 2-month-old and 38% in 3-month-old mice) by exposure to a carnitine palmitoyltransferase I inhibitor, etomoxir (1 micromol/l). Etomoxir failed to affect the insulin response to alpha-ketoisocaproate. The effect of etomoxir on glucose-induced insulin release was lost after culturing db/db islets in RPMI medium containing 22 mmol/l glucose but no fatty acid. Culture of db/+ islets with 0.125 mmol/l palmitate led to a decrease in glucose-induced insulin secretion, which was partially reversible by etomoxir. Both islet glucose oxidation and the ratio of glucose oxidation to utilization were decreased in db/db islets. Etomoxir significantly enhanced glucose oxidation by 60% and also the ratio of oxidation to glucose utilization (from 27 +/- 2.5 to 37 +/-3.0%, P < 0.05). Pyruvate dehydrogenase (PDH) activity was decreased in islets of db/db mice (75 +/-4.2 vs. 91 +/- 2.9 nU/ng DNA, P < 0.01), whereas PDH kinase activity was increased (rate of PDH inactivation -0.25 +/- 0.02 vs. - 0.11 +/- 0.02/min, P < 0.0 1). These abnormalities were partly but not wholly reversed by a 2-h preexposure to etomoxir. In conclusion, elevated FFA levels in the db/db mouse diminish glucose-induced insulin secretion by a glucose-fatty acid cycle in which fatty acid oxidation inhibits glucose oxidation by decreasing PDH activity and increasing PDH kinase activities.
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PMID:A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse. 862 Oct 7

In the rat, the gene for liver mitochondrial carnitine palmitoyltransferase I (CPT I), though dormant prior to birth, is rapidly activated postnatally. We sought to elucidate which hormonal and/or nutritional factors might be responsible for this induction. In cultured hepatocytes from 20-day-old rat fetus, the concentration of CPT I mRNA, which initially was very low, increased dramatically in a dose-dependent manner after exposure of the cells to dibutyryl cAMP (Bt2cAMP). Similar results were obtained when long-chain fatty acids (LCFA), but not medium-chain fatty acids, were added to the culture medium. The effects of Bt2cAMP and LCFA were antagonized by insulin, also dose dependently. In contrast, CPT II gene expression, which was already high in fetal hepatocytes, was unaffected by any of the above manipulations. Bt2cAMP stimulated CPT I gene expression even when endogenous triacylglycerol breakdown was suppressed by lysosomotropic agents suggesting that the actions of cAMP and LCFA were distinct. Moreover, half-maximal concentrations of Bt2cAMP and linoleate produced an additive effect CPT I mRNA accumulation. While linoleate and Bt2cAMP stimulated CPT I gene transcription by twofold and fourfold, respectively, the fatty acid also increased the half-life of CPT I mRNA (50%). When hepatocytes were cultured in the presence of 2-bromopalmitate, (which is readily converted by cells into its non-metabolizable CoA ester) CPT I mRNA accumulation was higher than that observed with oleate or linoleate. Similarly, the CPT I inhibitor, tetradecylglycidate, which at a concentration of 20 microM did not itself influence the CPT I mRNA level, enhanced the stimulatory effect of linoleate. The implication is that induction of the CPT I message by LCFA does not require mitochondrial metabolism of these substrates; however, formation of their CoA esters is a necessary step. Unlike linoleate, the peroxisome proliferator, clofibrate, increased both CPT I and CPT II mRNA levels and neither effect was offset by insulin. It thus appears that the mechanism of action of LCFA differs from that utilized by clofibrate, which presumably works through the peroxisome proliferator activated receptor. We conclude that the rapid increase in hepatic CPT I mRNA level that accompanies the fetal to neonatal transition in the rat is triggered by the reciprocal change in circulating insulin and LCFA concentrations, coupled with elevation of the liver content of cAMP.
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PMID:Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes. 865 30

The Flux Control Coefficients of mitochondrial outer membrane carnitine palmitoyltransferase (CPT I) with respect to the overall rates of beta-oxidation, ketogenesis and tricarboxylic acid cycle activity were measured in hepatocytes isolated from rats in different metabolic states (fed, 24 h-starved, starved-refed and starved/insulin-treated). These conditions were chosen because there is controversy as to whether, when significant control ceases to be exerted by CPT I over the rate of fatty oxidation [Moir and Zammit (1994) Trends Biochem. Sci. 19, 313-317], this is transferred to one or more steps proximal to acylcarnitine synthesis (e.g. decreased delivery of fatty acids to the liver) or to the reaction catalysed by mitochondrial 3-hydroxy-3-methyl-glutaryl-CoA synthase [Hegardt (1995) Biochem. Soc. Trans. 23, 486-490]. Therefore isolated hepatocytes were used in the present study to exclude the involvement of changes in the rate of delivery of non-esterified fatty acids (NEFA) to the liver, such as occur in vivo, and to ascertain whether, under conditions of constant supply of NEFA, CPT I retains control over the relevant fluxes of fatty acid oxidation to ketones and carbon dioxide, or whether control is transferred to another (intrahepatocytic) site. The results clearly show that the Flux Control Coefficients of CPT I with respect to overall beta-oxidation and ketogenesis are very high under all conditions investigated, indicating that control is not lost to another intrahepatic site during the metabolic transitions studied. The control of CPT I over tricarboxylic acid cycle activity was always very low. The significance of these findings for the integration of fatty acid and carbohydrate metabolism in the liver is discussed.
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PMID:Flux control exerted by mitochondrial outer membrane carnitine palmitoyltransferase over beta-oxidation, ketogenesis and tricarboxylic acid cycle activity in hepatocytes isolated from rats in different metabolic states. 876 Mar 64


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