Primary and secondary alterations of neonatal carnitine metabolism
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Coenzyme A
The activities of palmitoyl-coenzyme A (CoA) synthetase, carnitine acetyltransferase (CAT), and carnitine palmitoyltransferase (CPT) and the levels of ketone bodies, reduced coenzyme A (CoASH), carnitine, and their esters, which are involved in fatty acid metabolism, in rat liver and plasma were measured after the administration of Escherichia coli lipopolysaccharide (LPS). We also studied the effect of L-carnitine treatment before LPS administration on survival and on hepatic fatty acid metabolism. The activities of CAT and CPT and the concentrations of ketone bodies, CoA, and carnitine derivatives (except for malonyl-CoA) declined in the liver after LPS administration. The activity of palmitoyl-CoA synthetase was changed little after LPS administration, and the level of hepatic malonyl-CoA increased significantly, suggesting that LPS causes activated fatty acids to undergo esterification and lipogenesis rather than oxidation. Treatment of rats with L-carnitine before LPS greatly increased the survival rate, but did not affect enzymes that metabolize fatty acids, CoA, or carnitine derivatives in the liver. Further studies are necessary to elucidate the mechanism of the effect of carnitine on post-LPS survival.
Coenzyme A
Lipogenesis
Fatty Acid Metabolism
Malonyl-CoA
Carnitine O-palmitoyltransferase
Acyl-CoA
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The relationship between the concentration of carnitine and the oxidation of oleate was examined in homogenates prepared from skeletal muscle, liver, kidney, and heart of the rat, and from canine and human skeletal muscle. The carnitine content of these tissues in situ spanned a wide range, from about 0.1 μmol per gram in rat liver to about 3.0 μmol per gram in human muscle. The concentration of carnitine required for half-maximal rates of fatty acid oxidation in vitro also varied greatly (10 to 15 μM for rat liver to 200 to 400 μM for human muscle), and in rough proportion to the normal carnitine content of the tissues. For any given tissue, the carnitine content seems to be set at a level necessary for optimal rates of fatty acid oxidation. The data provide a plausible explanation for the fact that muscle fatty acid metabolism is severely impaired in the syndrome of human carnitine deficiency, since measured carnitine levels are in the range expected to limit substantially the capacity for fatty acid oxidation.
Fatty Acid Metabolism
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In order to evaluate the protective effects of L-carnitine on ischemic myocardium, its effects on tissue levels of acyl carnitine, acyl coenzyme A (CoA) and high energy phosphate were studied in ischemic dog hearts. Myocardial ischemia was induced by the ligation of left anterior descending coronary artery for 15 minutes. L-carnitine ( 100 mg/kg) was administered intravenously prior to coronary ligation. In ischemic myocardium, tissue levels of free carnitine decreased from 1043 ± 358 to 623 ± 180 n mol/g (p<0.001). On the other hand, long chain acyl carnitine increased from 214 ± 54 to 498 ± 149 n mol/g (p<0.001) and long chain acyl CoA increased from 15.7 ± 4.8 to 23.2 ± 5.4 n mol/g (p<0.01 ). Pretreatment of L-carnitine increased tissue levels of free carnitine to 863 ± 318 n mol/g (p<0.005) and decreased long chain acyl carnitine and long chain acyl CoA to 368 ±128 n mol/g (p<0.02) and 19.2 ± 6.5 n mol/g (p<0.1) respectively. Tissue levels of adenosine triphosphate (ATP) that was reduced by myocardial ischemia from 5.43± 0.67 to 2.80 ± 0.58 μ mol/g (p<0.001) was increased to 3.28 ± 0.63 μ mol/g (p< 0.02) by L-carnitine. Positive correlation was observed between ATP and free carnitine (p<0.01). On the other hand, negative correlation was observed not only between ATP and the ratio of long chain acyl CoA to free carnitine but also between ATP and the ratio of long chain acyl carnitine to free carnitine (p<0.01 respectively). These results suggest that the accumulation of long chain acyl carnitine may play an important role on cellular damage in ischemic myocardium and that administration of exogenous L-carnitine is beneficial for the protection of ischemic myocardium, probably because it reduces the accumulation of long chain acyl carnitine as well as long chain acyl CoA.
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High-energy phosphate
Mole
Adenosine triphosphate
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Coenzyme A
DTNB
Acetylcarnitine
Acetyl-CoA
Acyl-CoA
Acetyltransferases
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Carbohydrate Metabolism
Fatty Acid Metabolism
Coenzyme A
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CARNITINE (β-hydroxy-γ-trimethylaminobutyric acid) is an essential cofactor for the oxidation of fatty acids by mitochondria. It serves to carry long-chain fatty acids in the form of their acyl-carnitine esters across the barrier of the inner mitochondrial membrane before β-oxidation. Since 1973,1 a total of 46 patients have been described with evidence of impaired fatty acid oxidation associated with reduced levels of carnitine.2 These patients have been divided into a group with a "systemic carnitine deficiency," which presents in infancy or early childhood with recurrent episodes of coma and hypoglycemia, and a group with a "muscle carnitine deficiency," which presents later . . .
Coenzyme A
Carnitine O-palmitoyltransferase
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Carnitine O-palmitoyltransferase
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Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Anaerobic glycolysis
Carbohydrate Metabolism
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The relationship between the acid-soluble carnitine and coenzyme A pools was studied in fed and 24-h-starved rats after carnitine administration. Carnitine given by intravenous injection at a dose of 60μmol/100g body wt. was integrated into the animal's endogenous carnitine pool. Large amounts of acylcarnitines appeared in the plasma and liver within 5min of carnitine injection. Differences in acid-soluble acylcarnitine concentrations were observed between fed and starved rats after injection and reflected the acylcarnitine/carnitine relationship seen in the endogenous carnitine pool of the two metabolic states. Thus, a larger acylcarnitine production was seen in starved animals and indicated a greater source of accessible acyl-CoA molecules. In addition to changes in the amount of acylcarnitines present, the specific acyl groups present also varied between groups of animals. Acetylcarnitine made up 37 and 53% of liver acid-soluble acylcarnitines in uninjected fed and starved animals respectively. At 5min after carnitine injection hepatic acid-soluble acylcarnitines were 41 and 73% in the form of acetylcarnitine in fed and starved rats respectively. Despite these large changes in carnitine and acylcarnitines, no changes were observed in plasma non-esterified fatty acid or β-hydroxybutyrate concentrations in either fed or starved rats. Additionally, measurement of acetyl-CoA, coenzyme A, total acid-soluble CoA and acid-insoluble CoA demonstrated that the hepatic CoA pool was resistant to carnitine-induced changes. This lack of change in the hepatic CoA pool or ketone-body production while acyl groups are shunted from acyl-CoA molecules to acylcarnitines suggests a low flux through the carnitine pool compared with the CoA pool. These results support the concept that the carnitine/acid-soluble acylcarnitine pool reflects changes in, rather than inducing changes in, the hepatic CoA/acyl-CoA pool.
Acetylcarnitine
Coenzyme A
Acyl-CoA
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Diastereomer
Fatty Acid Metabolism
Carnitine palmitoyltransferase I
Carnitine O-palmitoyltransferase
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