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)

This study was designed to determine if acute (in vitro) or chronic (in vivo) adriamycin inhibits cardiac fatty acid oxidation and if so at what sites in the fatty acid oxidation pathway. In addition, the role of L-carnitine in reversing or preventing this effect was examined. We determined the effects of adriamycin in the presence or absence of L-carnitine on the oxidation of the metabolic substrates [1-14C]palmitate. [1(-14)C] octanoate. [1(-14)C]butyrate, [U-14C]glucose, and [2(-14)C]pyruvate in isolated cardiac myocytes. Acute exposure to adriamycin caused a concentration- and time-dependent inhibition of carnitine palmitoyl transferase 1 (CPT 1) dependent long-chain fatty acid, palmitate, oxidation. Chronic exposure to (18 mg/kg) adriamycin inhibited palmitate oxidation 40% to a similar extent seen in vitro with 0.5 mM adriamycin. Acute or chronic administration of L-carnitine completely abolished the adriamycin-induced inhibition of palmitate oxidation. Interestingly, medium- and short-chain fatty acid oxidation, which are independent of CPT 1, were also inhibited acutely by adriamycin and could be reversed by L-carnitine. In isolated rat heart mitochondria, adriamycin significantly decreased oxidation of the CPT 1 dependent substrate palmitoyl-CoA by 50%. However, the oxidation of a non-CPT 1 dependent substrate palmitoylcarnitine was unaffected by adriamycin except at concentrations greater than 1 mM. These data suggest that after in vitro or in vivo administration, adriamycin, inhibits fatty acid oxidation in part secondary to inhibition of CPT 1 and/or depletion of its substrate, L-carnitine, in cardiac tissue. However, these findings also suggest that L-carnitine plays an additional role in fatty acid oxidation independent of CPT 1 or fatty acid chain length.
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PMID:Acute and chronic effects of adriamycin on fatty acid oxidation in isolated cardiac myocytes. 914 Aug 35

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.
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PMID:Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle. 914 86

Energy deprivation, as a result of aglycemia, leads to depression of the central synaptic transmission. Endogenous adenosine has been implicated in this depressant effect. We have studied the possible involvement of endogenous adenosine in the depression of corticostriatal excitatory transmission induced by glucose deprivation by using intracellular recordings in brain slices. After stimulation of corticostriatal fibers, EPSPs were recorded from striatal spiny neurons. Adenosine (3-300 microM) or brief periods (5-10 min) of aglycemia reduced the EPSP amplitude but did not alter the membrane potential and the resistance of the recorded cells. These inhibitory effects were not associated with an alteration of the postsynaptic sensitivity to exogenous glutamate but were coupled with an increased paired-pulse facilitation, suggesting the involvement of presynaptic mechanisms. A delayed postsynaptic membrane depolarization/inward current was detected after 15-20 min of glucose deprivation. The presynaptic inhibitory effects induced by adenosine and aglycemia were both antagonized either by the nonselective adenosine receptor antagonist caffeine (2.5 mM) or by the A1 receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine (CPT, 1 microM) and 1,3-dipropyl-8-cyclopentylxanthine (CPX, 300 nM). Conversely, these antagonists affected neither the delayed membrane depolarization/inward current nor the underlying conductance increase produced by glucose deprivation. The ATP-sensitive potassium channel blockers tolbutamide (1 mM) and glipizide (100 nM) had no effect on the aglycemia-induced decrease of EPSP amplitude. Our data demonstrate that endogenous adenosine acting on A1 receptors mediates the presynaptic inhibition induced by aglycemia at corticostriatal synapses, whereas ATP-dependent potassium channels do not play a significant role in this presynaptic inhibition.
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PMID:Endogenous adenosine mediates the presynaptic inhibition induced by aglycemia at corticostriatal synapses. 916 11

We examined effects of temperature acclimation on ultrastructural characteristics of cardiac myocytes and maximal activities of metabolic enzymes in cardiac tissue of striped bass (Morone saxatilis). Ventricular mass and ventricular mass divided by body weight were significantly increased (29% and 40%, respectively) in animals acclimated to cold (5 degrees C) vs. warm temperatures (25 degrees C). Mean myocyte diameter was increased at cold temperature (3.47 +/- 0.14 vs. 2.98 +/- 0.08 microns), which is sufficient to explain the increase in ventricular mass. Ventricular enlargement did not alter volume densities of mitochondria, myofibrils, protein concentration, or citrate synthase activity. Thus total volume of mitochondria and myofibrils increased proportionately with cardiac mass in cold animals. Activities of hexokinase (34%) and carnitine palmitoyltransferase (42%) increased in cold animals, suggesting positive compensation and increased aerobic capacity for utilization of glucose and fatty acids for energy production. Enlargement of the ventricle and an increased capacity for ATP production in striped bass may help compensate for kinetic constraints at cold temperatures and maintain circulatory support to oxidative axial musculature for swimming activity.
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PMID:Structural and biochemical analyses of cardiac ventricular enlargement in cold-acclimated striped bass. 924 57

At least 90% of the 12 to 15 million persons with diabetes mellitus in the United States, half of whose condition remains undiagnosed, have type 2 diabetes. Type 2 diabetes is preceded by a long period of impaired glucose tolerance, a reversible metabolic state associated with increased prevalence of macrovascular complications. Thus, at the time of diagnosis, long-term complications have developed in almost one fourth of patients. Susceptibility to type 2 diabetes requires genetic (most likely polygenic) and acquired factors, and its pathogenesis involves an interplay of progressive insulin resistance and beta-cell failure. The ideal treatment of type 2 diabetes should reverse insulin resistance and beta-cell dysfunction in most treated patients and prevent, delay, or reverse long-term complications. Current strategies are aimed at amelioration of insulin resistance (diet, exercise, weight loss, and metformin and troglitazone therapy), augmentation of insulin supply (sulfonylurea and insulin therapy), or limitation of postprandial hyperglycemia (acarbose therapy). Future therapies probably will target (1) insulin resistance, using a multifaceted approach; (2) hepatic glucose production, using gluconeogenesis inhibitors; (3) excess nonesterified fatty acid production, using lipolysis inhibitors; and (4) fat oxidation, using carnitine palmitoyltransferase I and II inhibitors. Attempts also could be made to stimulate energy expenditure and increase nonoxidative glucose disposal by means of beta 3-adrenoceptor agonists. One promising strategy is an attack on multiple pathophysiological processes by combining antidiabetic agents with disparate mechanisms of action. Thus, we now have unprecedented resources for drug therapy for diabetes, with great opportunity for innovative combinations. It is hoped that these expanded choices will provide the tools necessary for a more efficient management of type 2 diabetes and prevention of its long-term complications.
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PMID:Pathophysiology of type 2 diabetes and modes of action of therapeutic interventions. 948 41

We have studied the possible mechanisms underlying the decrease of excitatory transmission induced by glucose deprivation by using electrophysiological recordings in corticostriatal slices. Extracellular field potentials were recorded in the striatum after cortical stimulation; these potentials were progressively reduced by glucose deprivation. The reduction started 5 minutes after the onset of aglycemia. The field potential was fully suppressed after 40 minutes of glucose deprivation. After the washout of the aglycemic solution only a partial recovery was observed. Aglycemia also induced a delayed inward current during single-microelectrode voltage-clamp recordings from spiny neurons. This inward current was coupled with an increased membrane conductance. The A1 adenosine receptor antagonists, 8-cyclopentyl-1,3-dimethylxanthine (CPT, 1 micromol/L) and 1,3-dipropyl-8-cyclopentylxanthine (CPX, 300 nmol/L), significantly reduced the aglycemia-induced decrease of field potential amplitude. Moreover, in the presence of CPT and CPX, a full recovery of the field potential amplitude after the interruption of the aglycemic solution was observed. Conversely, these antagonists affected neither the inward current nor the underlying conductance increase produced by glucose deprivation. The ATP-sensitive potassium channel blockers glibenclamide (10 micromol/L) and glipizide (100 nmol/L) had no effect on the aglycemia-induced decrease of the field potential amplitude. We suggest that endogenous adenosine, but not ATP-dependent potassium channels, plays a significant role in the aglycemia-induced depression of excitatory transmission at corticostriatal synapses probably through a presynaptic mechanism. Moreover, adenosine is not involved in the postsynaptic changes induced by glucose deprivation in spiny striatal neurons.
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PMID:A possible mechanism for the aglycemia-induced depression of glutamatergic excitation in the striatum. 934 37

The present studies examined the development of ingestive responsiveness to blockade of fatty acid oxidation in rat pups using 2-mercaptoacetate (MA), an inhibitor of mitochondrial acyl-coenzyme A dehydrogenases, or methyl palmoxirate (MP), an inhibitor of carnitine palmitoyltransferase I (CPT-I). Rat pups aged 6, 9, 12, or 15 days of age received an intraperitoneal injection of 0, 100, 200, 400, or 800 mumol/kg MA, and intake of a commercial half-and-half or 15% glucose diet from the floor of test containers was assessed in a 30-min test beginning 1 h after administration of MA. The results demonstrate that, although no dose of MA affected intake of either diet in pups 9 days or younger, low doses of MA increased intake and the highest dose suppressed intake of both diets in pups 12 days of age or older. Physiological measurements indicated that levels of beta-hydroxybutyrate were significantly lower following doses of 400 or 800 mumol/kg MA in 9-, 12-, and 15-day-old pups and that gastric emptying was inhibited in 12 and 15 day olds by 800 mumol/kg MA. Intake of a commercial half-and-half diet from the floor of test containers was also assessed in 12- to 18-day-old rat pups 6.5 h after they received a gavage load of 0, 1.25, 2.5, 5, or 10 mg/kg MP. Unlike MA, MP did not increase intake of a commercial half-and-half diet in rat pups 12 or 15-18 days of age; instead, the highest dose of MP suppressed intake in 15- to 18-day-old pups. The failure of MP to enhance intake in pups at the ages tested is likely related to composition of dam's milk; rat milk is high in medium-chain fatty acids that do not require CPT-I for entry into mitochondria. Thus it is likely that MP does not significantly block fatty acid oxidation in pups at the ages tested. On the other hand, blockade of fatty acid oxidation produced by MA significantly affects intake by 12 days of age, suggesting it may be the first metabolic signal that influences intake in rat pups.
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PMID:Development of independent ingestive responding to blockade of fatty acid oxidation in rats. 937 5

In normoxic conditions, myocardial glucose utilization is inhibited when alternative oxidizable substrates are available. In this work we show that this inhibition is relieved in the presence of cAMP, and we studied the mechanism of this effect. Working rat hearts were perfused with 5.5 mM glucose alone (controls) or together with 5 mM lactate, 5 mM beta-hydroxybutyrate, or 1 mM palmitate. The effects of 0.1 mM chlorophenylthio-cAMP (CPT-cAMP), a cAMP analogue, were studied in each group. Glucose uptake, flux through 6-phosphofructo-1-kinase, and pyruvate dehydrogenase activity were inhibited in hearts perfused with alternative substrates, and addition of CPT-cAMP completely relieved the inhibition. The mechanism by which CPT-cAMP induced a preferential utilization of glucose was related to an increased glucose uptake and glycolysis, and to an activation of phosphorylase, pyruvate dehydrogenase, and 6-phosphofructo-2-kinase, the enzyme responsible for the synthesis of fructose 2,6-bisphosphate, the well-known stimulator of 6-phosphofructo-1-kinase. In vitro phosphorylation of 6-phosphofructo-2-kinase by cAMP-dependent protein kinase increased the Vmax of the enzyme and decreased its sensitivity to the inhibitor citrate. Therefore, in hearts perfused with various oxidizable substrates, cAMP induces a preferential utilization of glucose by a concerted stimulation of glucose transport, glycolysis, glycogen breakdown, and glucose oxidation.
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PMID:Cyclic AMP suppresses the inhibition of glycolysis by alternative oxidizable substrates in the heart. 943 11

It is widely held that although obesity and type 2 diabetes are polygenic in origin, the primary defect causing both conditions is insulin resistance, which in turn gives rise to a constellation of other abnormalities, including hyperinsulinemia, dyslipidemia, glucose intolerance, and (in the genetically predisposed) frank hyperglycemia. Explored here is an alternative, albeit speculative, scenario in which hyperinsulinemia and insulin resistance arise either simultaneously or sequentially from some preexisting defect within the leptin signaling pathway. In either case, a central component of the model is that the breakdown of glucose homeostasis that is characteristic of the condition of obesity with type 2 diabetes is secondary to disturbances in lipid dynamics. The possibility is raised that abnormally high concentrations of malonyl-CoA in liver and skeletal muscle suppress the activity of mitochondrial carnitine palmitoyltransferase I and thus fatty acid oxidation in both sites. It is suggested that the buildup of fat within the muscle cell (caused in part by excessive delivery of VLDLs from the liver) interferes with glucose transport or metabolism or both, producing insulin resistance. Elevated circulating concentrations of fatty acids are also implicated in the etiology of type 2 diabetes by virtue of 1) their powerful acute insulinotropic effect, 2) their ability to exacerbate insulin resistance in muscle, and 3) their long-term detrimental action on pancreatic beta-cell function.
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PMID:Glucose-fatty acid interactions in health and disease. 949 60

Carnitine palmitoyltransferase-I (CPT-I) plays a crucial role in regulating cardiac fatty acid oxidation which provides the primary source of energy for cardiac muscle contraction. CPT-I catalyzes the transfer of long chain fatty acids into mitochondria and is recognized as the primary rate controlling step in fatty acid oxidation. Molecular cloning techniques have demonstrated that two CPT-I isoforms exist as genes encoding the 'muscle' and 'liver' enzymes. Regulation of fatty acid oxidation rates depends on both short-term regulation of enzyme activity and long-term regulation of enzyme synthesis. Most early investigations into metabolic control of fatty acid oxidation at the CPT-I step concentrated on the hepatic enzyme which can be inhibited by malonyl-CoA and can undergo dramatic amplification or reduction of its sensitivity to inhibition by malonyl-CoA. The muscle CPT-I is inherently more sensitive to malonyl-CoA inhibition but has not been found to undergo any alteration of its sensitivity. Short-term control of activity of muscle CPT-I is apparently regulated by malonyl-CoA concentration in response to fuel supply (glucose, lactate, pyruvate and ketone bodies). The liver isoform is the only CPT-I enzyme present in the mitochondria of liver, kidney, brain and most other tissues while muscle CPT-I is the sole isoform expressed in skeletal muscle as well as white and brown adipocytes. The heart is unique in that it contains both muscle and liver isoforms. Liver CPT-I is highly expressed in the fetal heart, but at birth its activity begins to decline whereas the muscle isoform, which is very low at birth, becomes the predominant enzyme during postnatal development. In this paper, the differential regulation of the two CPT-I isoforms at the protein and the gene level will be discussed.
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PMID:Differential regulation in the heart of mitochondrial carnitine palmitoyltransferase-I muscle and liver isoforms. 954 27


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