Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of Etomoxir as a carnitine palmitoyl transferase I-inhibitor was investigated in normal and chronic diabetic rats. Etomoxir (18 mg/kg) was given daily for 8 days by intraperitoneal injection in order to inhibit the oxidation of fatty acids and to increase the metabolism of glucose. This carnitine palmitoyl transferase I-inhibitor significantly improved and almost normalized the decreased heart function in chronic diabetic rats. Additionally to the improvement of ventricular heart function, alterations in the conducting system of the diabetic heart were significantly ameliorated. The serum concentrations of glucose, glycerol, cholesterol, tricylglycerol, phospholipids, and beta-hydroxybutyrate were significantly lower in comparison to untreated diabetic animals, while the serum concentration of free fatty acids markedly increased. In addition to the improvement of ventricular heart function, the carnitine content of heart and liver increased in the Etomoxir-treated rats. On the other hand, the lipid content of heart and liver increased in the Etomoxir-treated rats. On the other hand, the lipid content of heart and liver increased significantly. Thus, Etomoxir may be valuable not only as a potential anti-diabetic drug but also as a lipid-lowering agent for the treatment of diabetic related dyslipoproteinaemias and, in addition, as an agent in the treatment of diabetic cardiomyopathy. However, a long-term evaluation of the metabolic consequences of the blocked carnitine palmitoyltransferase I is necessary.
 ...
PMID:Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl transferase inhibitor Etomoxir. 875 Jul 78

Fasting inhibits glucose-induced insulin secretion. We investigated the role of a glucose fatty acid cycle for such inhibition and its molecular basis in pancreatic islets from 48-h fasted rats. The fasting-impaired insulin response to 27 mM glucose was restored by 41% with a carnitine palmitoyltransferase I inhibitor, etomoxir. Etomoxir also restored (by 50%) impaired glucose oxidation in islets from fasted rats and increased the ratio of oxidation to glycolytic flux from 33 to 43%. Fasting decreased total pyruvate dehydrogenase (PDH) activity (active, unphosphorylated plus inactive, phosphorylated form) by 29%, as well as the percentage of active form (54 +/- 5 vs. 79 +/- 2% in fed rats, P < 0.001). Fasting increased islet PDH kinase activity as follows: PDH-bound activity by 36% and free (not PDH bound) PDH kinase by 70%. Fasting failed to affect PDH kinase content when assayed by an enzyme-linked immunoabsorbent assay with antibodies raised against 45 kDa PDH kinase alpha-chain. We conclude that fasting impairs B cell function to a major extent through the operation of a glucose fatty acid cycle and that decreased PDH activity resulting from increased specific activity of PDH kinase constitutes an important molecular mechanism.
 ...
PMID:Fasting and decreased B cell sensitivity: important role for fatty acid-induced inhibition of PDH activity. 876 83

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
 ...
PMID:Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. 886 61

The heart is known for its ability to produce energy from fatty acids (FA) because of its important beta-oxidation equipment, but it can also derive energy from several other substrates including glucose, pyruvate, and lactate. The cardiac ATP store is limited and can assure only a few seconds of beating. For this reason the cardiac muscle can adapt quickly to the energy demand and may shift from a 100% FA-derived energy production (after a lipid-rich food intake) or any balanced situation (e.g., diabetes, fasting, exercise). These situations are not similar for the heart in terms of oxygen requirement because ATP production from glucose is less oxygen-consuming than from FA. The regulation pathways for these shifts, which occur in physiologic as well as pathologic conditions (ischemia-reperfusion), are not yet known, although both insulin and pyruvate dehydrogenase activation are clearly involved. It becomes of strategic importance to clarify the pathways that control these shifts to influence the oxygen requirement of the heart. Excess FA oxidation is closely related to myocardial contraction disorders characterized by increased oxygen consumption for cardiac work. Such an increased oxygen cost of cardiac contraction was observed in stunned myocardium when the contribution of FA oxidation to oxygen consumption was increased. In rats, an increase in n-3 polyunsaturated FA in heart phospholipids achieved by a fish-oil diet improved the recovery of pump activity during postischemic reperfusion. This was associated with a moderation of the ischemia-induced decrease in mitochondrial palmitoylcarnitine oxidation. In isolated mitochondria at calcium concentrations close to that reported in ischemic cardiomyocytes, a futile cycle of oxygen wastage was reported, associated with energy wasting (constant AMP production). This occurs with palmitoylcarnitine as substrate but not with pyruvate or citrate. The energy wasting can be abolished by CoA-SH and other compounds, but not the oxygen wasting. Again, the calcium-induced decrease in mitochondrial ADP/O ratio was reduced by increasing the n-3 polyunsaturated FA in the mitochondrial phospholipids. These data suggest that in addition to the amount of circulating lipids, the quality of FA intake may contribute to heart energy regulation through the phospholipid composition. On the other hand, other intervention strategies can be considered. Several studies have focused on palmitoylcarnitine transferase I to achieve a reduction in beta-oxidation. In a different context, trimetazidine was suggested to exert its anti-ischemic effect on the heart by interfering with the metabolic shift, either at the pyruvate dehydrogenase level or by reducing the beta-oxidation. Further studies will be required to elucidate the complex system of heart energy regulation and the mechanism of action of potentially efficient molecules.
 ...
PMID:Fatty acid oxidation in the heart. 889 66

The activity of hepatic fatty acid oxidation enzymes in rats fed linseed and perilla oils rich in alpha-linolenic acid (alpha-18:3) was compared to that in rats fed safflower oil rich in linoleic acid (18:2) and a saturated fat (palm oil). Palm and safflower oils were essentially devoid of alpha-18:3. The palmitoyl-CoA oxidation rates both in mitochondrial and peroxisomal pathways in liver homogenates were significantly higher in rats fed linseed oil than in those fed palm and safflower oils. Among rats fed diets containing palm oil, safflower oil, fat mixtures composed of safflower and perilla oils (2:1, w/w and 1:2, w/w), and perilla oil, mitochondrial and peroxisomal fatty oxidation rates increased with increasing dietary levels of perilla oil. Compared to palm and safflower oils, dietary alpha-18:3 either in the form of linseed or perilla oils profoundly increased the activity of carnitine palmitoyltransferase, acyl-CoA oxidase, 3-ketoacyl-CoA thiolase, and 2,4-dienoyl-CoA reductase. Smaller but significant increases by dietary alpha-18:3 of the activity of acyl-CoA dehydrogenase, enoyl-CoA hydratase, and delta 3, delta 2-enoyl-CoA isomerase were also observed. Unexpectedly, dietary alpha-18:3 greatly reduced the activity of 3-hydroxy-acyl-CoA dehydrogenase. Compared to palm oil, dietary polyunsaturated fats significantly reduced the activity of fatty acid synthetase and glucose-6-phosphate dehydrogenase to the same levels. The activity of pyruvate kinase was significantly higher in rats fed palm oil than in those fed polyunsaturated fats. The extent of reduction was more prominent with polyunsaturated fats containing alpha-18:3 than with safflower oil devoid of alpha-18:3. Thus, compared to linoleic acid and saturated fatty acids, dietary alpha-18:3 caused characteristic changes in the activity of hepatic enzymes in fatty acid and glucose metabolism in rats.
 ...
PMID:Activity of hepatic fatty acid oxidation enzymes in rats fed alpha-linolenic acid. 895 34

We tested the hypothesis that diabetes impairs myocardial glucose uptake and pyruvate oxidation under normal conditions and during a dobutamine-induced increase in work. We also tested the hypothesis that an increase in work would result in a decrease in the levels of malonyl CoA, a potent inhibitor of carnitine palmitoyltransferase I (CPT I). Streptozotocin-diabetic micropigs were compared with a nondiabetic control group (n = 8 per group). Triglyceride emulsion, glucose, and somatostatin were infused into the nondiabetic group to create an acute diabetic-like state. In accord with our hypothesis, malonyl CoA decreased significantly with dobutamine in both groups, providing a possible mechanism for increased fatty acid oxidation through relieved inhibition on CPT I. In the absence of dobutamine, glucose uptake and tracer-measured lactate uptake were decreased by 57 and 80%, respectively, in the diabetic group. Dobutamine infusion resulted in similar increases in cardiac contractility, oxygen consumption, and glucose uptake in both groups despite reductions of 50-65% in GLUT-4 and GLUT-1 protein in the diabetic group. Diabetic animals possessed a defect in myocardial pyruvate oxidation, as reflected in increased lactate production, and depressed lactate uptake and pyruvate dehydrogenase activity under control and dobutamine conditions. In conclusion, the major derangement in carbohydrate metabolism in diabetic myocardium was not in glycolysis but, rather, in pyruvate oxidation.
 ...
PMID:Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work. 899 89

Fatty acids are important metabolic substrates for the pancreatic beta-cell, and long term exposure of pancreatic islets to elevated concentrations of fatty acids results in an alteration of glucose-induced insulin secretion. Previous work suggested that exaggerated fatty acid oxidation may be implicated in this process by a mechanism requiring changes in metabolic enzyme expression. We have therefore studied the regulation of carnitine palmitoyltransferase I (CPT I) gene expression by fatty acids in the pancreatic beta-cell line INS-1 since this enzyme catalyzes the limiting step of fatty acid oxidation in various tissues. Palmitate, oleate, and linoleate (0.35 mM) elicited a 4-6-fold increase in CPT I mRNA. The effect was dose-dependent and was similar for saturated and unsaturated fatty acids. It was detectable after 1 h and reached a maximum after 3 h. The induction of CPT I mRNA by fatty acids did not require their oxidation, and 2-bromopalmitate, a nonoxidizable fatty acid, increased CPT I mRNA to the same extent as palmitate. The induction was not prevented by cycloheximide treatment of cells indicating that it was mediated by pre-existing transcription factors. Neither glucose nor pyruvate and various secretagogues had a significant effect except glutamine (7 mM) which slightly induced CPT I mRNA. The half-life of the CPT I transcript was unchanged by fatty acids, and nuclear run-on analysis showed a rapid (less than 45 min) and pronounced transcriptional activation of the CPT I gene by fatty acids. The increase in CPT I mRNA was followed by a 2-3-fold increase in CPT I enzymatic activity measured in isolated mitochondria. The increase in activity was time-dependent, detectable after 4 h, and close to maximal after 24 h. Fatty acid oxidation by INS-1 cells, measured at low glucose, was also 2-3-fold higher in cells cultured with fatty acid in comparison with control cells. Long term exposure of INS-1 cells to fatty acid was associated with elevated secretion of insulin at a low (5 mM) concentration of glucose and a decreased effect of higher glucose concentrations. It also resulted in a decreased oxidation of glucose. The results indicate that the CPT I gene is an early response gene induced by fatty acids at the transcriptional level in beta- (INS-1) cells. It is suggested that exaggerated fatty acid oxidation caused by CPT-1 induction is implicated in the process whereby fatty acids alter glucose-induced insulin secretion.
 ...
PMID:Fatty acids rapidly induce the carnitine palmitoyltransferase I gene in the pancreatic beta-cell line INS-1. 899 42

It is now clear that the availability of different metabolic substrates can have a profound influence on the extent of damage incurred during episodes of cardiac ischaemia, and on cardiac functional recovery on reperfusion following ischaemia. In particular, increases in fatty acid availability and oxidation, compared to glucose oxidation, under such conditions leads to a worsening of outcome. Therefore metabolic interventions aimed at enhancing glucose utilisation and pyruvate oxidation at the expense of fatty acid oxidation is a valid therapeutic approach to the treatment of myocardial ischaemia. In particular, the development of agents which will promote full glucose oxidation as opposed to glycolysis alone, offer clear advantages. This can be accomplished by different means, including direct or indirect inhibition of CPT-I or inhibition of fatty acid beta-oxidation, or by direct or indirect activation of PDH. It is not yet clear which of these approaches offers the best treatment of cardiac ischaemia. To date, trimetazidine and carnitine have received limited approval in Europe for the treatment of angina; large scale clinical trials with the other agents mentioned above have not been completed. The increasing availability of agents affecting these specific sites, and the increasingly sophisticated techniques for assessing myocardial metabolism, should allow elucidation of the optimum metabolic targets and development of novel pharmacological agents for the treatment of ischaemic heart disease.
 ...
PMID:Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. 907 87

Previous studies have reported the presence of carnitine palmitoyltransferase I and II in tumor cells and the inhibitory effects of fatty acids on cell proliferation. The present work considered the metabolic fate of [14C] or [3H]-labeled fatty acids and their effects on cellular metabolism in Hep2 human larynx tumor cells. The rate of uptake of acetate was 45% of that of myristate, palmitate, oleate, linoleate and arachidonate. However, acetate was rapidly metabolized within the cell as seen by its low rate of accumulation as non-esterified fatty acid, < 5% of that of the other fatty acids. The incorporation of fatty acids into neutral lipid fractions showed palmitate and oleate primarily entered the phospholipid fraction, while linoleate and arachidonate entered equally the phospholipid and triacylglycerol fractions. Palmitate and oleate were oxidized to 14CO2 at higher rates than linoleate and arachidonate, with arachidonate being the least oxidized of the unsaturated fatty acids. Acetate was oxidized at 10-30 fold higher rates than the other fatty acids. Palmitate, oleate, linoleate and arachidonate all had significant inhibitory effects on the rate of glucose utilization by Hep2 cells, ranging from 25-38% inhibition and were found to inhibit cell proliferation by 17-73%. These findings suggest that certain fatty acids not only play a structural role in cellular metabolism, but may also have a potential regulatory role in the glycolytic pathway of Hep2 cells.
 ...
PMID:Metabolic fate and effects of saturated and unsaturated fatty acids in Hep2 human larynx tumor cells. 909 Apr 68

The objective of the present work was the assessment of metabolic events responsible for the improvement of hemodynamic function of volume-overloaded hearts from rats receiving propionyl-L-carnitine. A severe cardiac hypertrophy was induced in 2-mo-old rats by surgical opening of an aortocaval communication. Three months later, during in vitro perfusions with 1.2 mM palmitate, 11 mM glucose, and 10 IU/l insulin, the mechanical performance and overall energy turnover (myocardial O2 consumption) of hypertrophied rat hearts were significantly decreased under conditions of moderate and high workloads. These changes in cardiac energetics paralleled the decrease in total tissue carnitine content and alterations in exogenous palmitate oxidation. The oxidative utilization of glucose was also slightly depressed in volume-overloaded hearts while steady-state glycolysis rates increased, especially in hearts subjected to high mechanical loads. This slowing of metabolic pathways involved in acetyl-CoA generation resulted in decreased NADH availability and in an apparent substrate limitation of oxidative phosphorylation suggested by a failure of cytosolic unbound ADP to drive respiration. Long-term administration of propionyl-L-carnitine normalized the degree of reduction of mitochondrial pyridine nucleotides and improved the kinetics of mitochondrial ATP production in volume-overloaded hearts. The resulting acceleration of energy turnover was essentially related to improved oxidative utilization of glucose, but steady-state palmitate oxidation rates also increased in severely hypertrophied hearts. This concomitant acceleration of glucose and palmitate oxidation may be related to the particular experimental conditions (high exogenous palmitate concentrations, elevated workloads) used in this study. We assume that the increase in intracellular carnitine, together with a stimulation of acetyl-CoA demands related to high workloads, creates conditions that are compatible with the simultaneous relief of pyruvate dehydrogenase and carnitine palmitoyltransferase I. The resulting increase in the rate of steady-state ATP production improves, in turn, the mechanical activity of volume-overloaded hearts.
 ...
PMID:Control of oxidative metabolism in volume-overloaded rat hearts: effect of propionyl-L-carnitine. 913 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>