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)

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

The theory of steady-state flux control was applied to characterize the regulation of beta-oxidation flux in uncoupled rat liver mitochondria oxidizing palmitoylcarnitine in the presence of rotenone, malonate and the beta-hydroxybutyrate/acetoacetate redox buffer. By titrations with inhibitors such as antimycin, myxothiazol, azide and 4-pentenoic acid, the flux control coefficients of the b-c1 complex, cytochrome c oxidase and thiolase, were determined experimentally. The flux control coefficients of carnitine palmitoyltransferase II, ETF:CoQ oxidoreductase and beta-hydroxybutyrate dehydrogenase were determined from elasticity coefficients obtained by measuring the flux dependencies of acyl-CoA and acetyl-CoA+CoASH concentrations, the electron transfer flavoprotein redox state, the CoQ redox state and the NAD redox state. It was found that at low flux rates the flux control was distributed mainly between acyl-CoA dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase (Ci = 0.89). At maximum flux rates, carnitine palmitoyltransferase II (Ci = 0.35) and thiolase (Ci = 0.13) contribute additionally to the flux control. Thus, the phenomena of regulation of mitochondrial beta-oxidation can be described as multistep control.
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PMID:Application of the theory of steady-state flux control to mitochondrial beta-oxidation. 166 35

In the absence of any exogenous substrates, glucagon (1 X 10(-9) M) stimulated 45Ca2+ efflux from perfused livers derived from fed rats but not in livers of 24-h-fasted animals. In livers of 24-h-fasted animals perfused under conditions which would decrease cellular NAD(P)H/NAD(P)+ ratio (pyruvate (2.0 mM) or acetoacetate (10.0 mM], glucagon (1 X 10(-9) M) did not stimulate 45Ca2+ efflux. Similarly, in livers of 24-h-fasted animals perfused with substrates which increase cellular NAD(P)H content (lactate (2.0 mM) or beta-hydroxybutyrate (10.0 mM], glucagon (1 X 10(-9) M) did not increase 45Ca2+ efflux. Glucagon (1 X 10(-9) M) elicited an increase in 45Ca2+ efflux from livers of 24-h-fasted animals, only when the livers were perfused with [lactate]/[pyruvate] and [beta-hydroxybutyrate]/[acetoacetate] ratios similar to those reported for livers of fed rats. Stimulation of 45Ca2+ efflux elicited by either 8-CPT-cAMP, a cAMP analog, or high glucagon concentrations (1 X 10(-8) M) was not affected whether livers were perfused with pyruvate (2.0 mM) or lactate (2.0 mM). Administration of isobutylmethylxanthine (50 microM) alone, or glucagon (1 X 10(-9) M) in the presence of isobutylmethylxanthine (50 microM) stimulated 45Ca2+ efflux from livers of 24-h-fasted animals perfused with pyruvate (2.0 mM) but not from livers perfused with lactate (2.0 mM). The ability of glucagon (1 X 10(-9) M) to elevate tissue cAMP levels was also regulated by the oxidation-reduction state of the livers. The data indicate that glucagon-stimulated 45Ca2+ efflux from perfused livers is mediated via cAMP and is dependent on the oxidation-reduction state of the livers.
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PMID:Glucagon-stimulated calcium efflux in the isolated perfused rat liver is dependent on cellular redox potential. 244 42

Peroxisomal and mitochondrial beta-oxidation of dicarboxylic acids (DCAs) were investigated and compared. When isolated hepatocytes were incubated with DCAs of various chain lengths, H2O2 was derived from peroxisomal beta-oxidation, the rates of its generation being comparable to those seen with monocarboxylic acids (MCAs), whereas the rates of ketone body production, a measure of mitochondrial beta-oxidation, were much lower than those with MCAs. Peroxisomal beta-oxidation measured by cyanide-insensitive NAD reduction exhibited similar chain-length specificities for both dicarboxylyl-CoAs (DC-CoAs) and monocarboxylyl-CoAs (MC-CoAs), except that the activities for DC-CoAs with 10-16 carbon atoms were about half of those of the corresponding MC-CoAs. In contrast, mitochondrial beta-oxidation measured by antimycin A-sensitive O2 consumption had no activity for DCAs. In the study with purified enzymes, the reactivities of mitochondrial carnitine palmitoyltransferase and acyl-CoA dehydrogenase for DC-CoAs were much lower than those for MC-CoAs, while the reactivity of peroxisomal acyl-CoA oxidase for DC-CoAs was comparable to that for the corresponding MC-CoAs. Accordingly, the properties of carnitine palmitoyltransferase and acyl-CoA dehydrogenase must be the rate-limiting factors for mitochondrial beta-oxidation, with the result that DCAs might hardly be oxidized in mitochondria. Comparative study of beta-oxidation capacities of peroxisomes and mitochondria in the liver showed that DC12-CoA was hardly subjected to mitochondrial beta-oxidation, and that the beta-oxidation of DCAs in rat liver, therefore, must be carried out exclusively in peroxisomes.
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PMID:Compartmentation of dicarboxylic acid beta-oxidation in rat liver: importance of peroxisomes in the metabolism of dicarboxylic acids. 291 48

Hepatocytes isolated from the periportal or perivenous zones of livers of fed rats were used to study the long-term (14 h) and short-term (2 h) effects of glucagon on gluconeogenesis and ketogenesis. Long-term culture with glucagon (100 nM) resulted in a greater increase (P less than 0.01) in gluconeogenesis in periportal than in perivenous cells (93 +/- 16 versus 30 +/- 14 nmol/h per mg of protein; 72% versus 30% increase), but short-term incubation (2 h) with glucagon resulted in similar stimulation in the two cell populations. Rates of ketogenesis (acetoacetate and D-3-hydroxybutyrate production) were not significantly higher in periportal cells cultured without glucagon, compared with perivenous cells. However, after long-term culture with glucagon, the periportal cells had a significantly higher rate of ketogenesis (from either palmitate or octanoate as substrate), but a lower 3-hydroxybutyrate/acetoacetate production ratio, suggesting a more oxidized mitochondrial NADH/NAD+ redox state despite the higher rate of beta-oxidation. Periportal hepatocytes had a higher activity of carnitine palmitoyltransferase but a lower activity of citrate synthase than did perivenous cells. These findings suggest that: (i) glucagon elicits greater long-term stimulation of gluconeogenesis in periportal than in perivenous hepatocytes maintained in culture; (ii) after culture with glucagon, the rates of ketogenesis and the mitochondrial redox state differ in periportal and perivenous hepatocytes.
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PMID:Glucagon regulation of gluconeogenesis and ketogenesis in periportal and perivenous rat hepatocytes. Heterogeneity of hormone action and of the mitochondrial redox state. 322

The oxidation of palmityl-coenzyme A and acetate to CO2 by mitochondria isolated from rat small intestine increases 10-fold at the time of weaning (18-21 days of age). Carnitine palmitoyltransferase (EC 2.3.1.21) activity is 2-fold greater in mitochondria of suckling rat intestine compared to postweaned intestine. These data indicate that carnitine palmitoyltransferase does not control the increase in intestinal fatty acid oxidation during weaning. We have previously reported that the estimated intramitochondrial [NADH]/[NAD+] as determined by the ratio of tissue levels of 3-hydroxybutyrate and acetoacetate is fivefold greater in suckling rat intestine compared to postwean animals. High intramitochondrial [NADH]/[NAD+] which is present in suckling rat small intestine is associated with a decrease in citric acid cycle activity and beta oxidation. The addition of acetoacetate causes a decrease in intramitochondrial [NADH]/[NAD+]. The oxidation of acetate and glucose to CO2 by suckling rat intestine mitochondria was stimulated by the addition of 1 mM acetoacetate. These data suggest that the lower rate of fatty acid oxidation by suckling rat small intestine is controlled by elevated intramitochondrial [NADH]/[NAD+].
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PMID:Control of fatty acid oxidation by intramitochondrial [NADH]/[NAD+] in developing rat small intestine. 335 71

The peroxisomal beta-oxidation of omega-phenyl fatty acids (PFAs) as model compounds for xenobiotic acyl compounds was investigated. In isolated hepatocytes, omega-phenyllauric acid (PFA12) was chain-shortened to PFAs having an even number of carbon atoms in the acyl side chain. Associated with this reaction, H2O2 generation was observed, the rate of which was markedly enhanced by clofibrate treatment of rats. Also when using isolated peroxisomes, such a chain-shortening of PFA12 occurred, associated with stoichiometrical production of NADH and acetyl-CoA. The CoA-ester form of PFA12 as a substrate and NAD as a cofactor were required in this reaction, indicating the participation of peroxisomal beta-oxidation in the chain-shortening of PFA12. When using PFAs with various chain lengths, the rates of H2O2 generation measured as the peroxisomal beta-oxidation in isolated hepatocytes were similar to those with the corresponding fatty acids, whereas the rates of ketone body production measured as the mitochondrial beta-oxidation were much lower than that with any fatty acid examined. From the study with isolated mitochondria and purified enzymes, it was found that the mitochondrial beta-oxidation of PFAs was carnitine-dependent, and that the activities of carnitine palmitoyltransferase for PFA-CoAs are low. Moreover, the activities of acyl-CoA dehydrogenase for PFA-CoAs were lower than those for fatty acyl-CoAs, while the activities of acyl-CoA oxidase for PFA-CoAs were comparable to those for fatty acyl-CoAs. As a result, relatively long chain PFAs were hardly subjected to mitochondrial beta-oxidation. Based on the maximum enzyme activities of the beta-oxidation, which were measured by following acyl-CoA-dependent NAD reduction in isolated peroxisomes and O2 consumption in isolated mitochondria, about 60% of the beta-oxidation of PFA12 in the rat liver was peroxisomal. In clofibrate-treated rats, the value reached about 85%. From these results it is concluded that the peroxisome is one of the important sites of degradation of xenobiotic acyl compounds.
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PMID:Participation of peroxisomes in the metabolism of xenobiotic acyl compounds: comparison between peroxisomal and mitochondrial beta-oxidation of omega-phenyl fatty acids in rat liver. 365 89

Livers of genetically obese Zucker rats showed, compared with lean controls, hypertrophy and enrichment in triacylglycerols, indicating that fatty acid metabolism was directed towards lipogenesis and esterification rather than towards fatty acid oxidation. Mitochondrial activities of cytochrome c oxidase and monoamine oxidase were significantly lower when expressed per g wet wt. of liver, whereas peroxisomal activities of urate oxidase and palmitoyl-CoA-dependent NAD+ reduction were unchanged. Liver mitochondria were able to oxidize oleic acid at the same rate in both obese and lean rats. For reactions occurring inside the mitochondria, e.g. octanoate oxidation and palmitoyl-CoA dehydrogenase, no difference was found between both phenotypes. Total carnitine palmitoyl-, octanoyl- and acetyl-transferase activities were slightly higher in mitochondria from obese rats, whereas the carnitine content of both liver tissue and mitochondria was significantly lower in obese rats compared with their lean littermates. The carnitine palmitoyltransferase I activity was slightly higher in liver mitochondria from obese rats, but this enzyme was more sensitive to malonyl-CoA inhibition in obese than in lean rats. The above results strongly suggest that the impaired fatty acid oxidation observed in the whole liver of obese rats is due to the diminished transport of fatty acids across the mitochondrial inner membrane via the carnitine palmitoyltransferase I. This effect could be reinforced by the decreased mitochondrial content per g wet wt. of liver. The depressed fatty acid oxidation may explain in part the lipid infiltration of liver observed in obese Zucker rats.
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PMID:Study of some factors controlling fatty acid oxidation in liver mitochondria of obese Zucker rats. 380 Sep 70

The effects of the glucocorticoid dexamethasone on fatty acid and pyruvate metabolism were studied in rat hepatocyte cultures. Parenchymal hepatocytes were cultured for 24 h with nanomolar concentrations of dexamethasone in either the absence or the presence of insulin (10 nM) or dibutyryl cyclic AMP (1 microM BcAMP). Dexamethasone (1-100 nM) increased the rate of formation of ketone bodies from 0.5 mM-palmitate in both the absence and the presence of BcAMP, but inhibited ketogenesis in the presence of insulin. Dexamethasone increased the proportion of the palmitate metabolized that was partitioned towards oxidation to ketone bodies, and decreased the cellular [glycerol 3-phosphate]. The latter suggests that the increased partitioning of palmitate to ketone bodies may be associated with decreased esterification to glycerolipid. The Vmax. of carnitine palmitoyltransferase (CPT) and the affinity of CPT for palmitoyl-CoA were not affected by dexamethasone, indicating that the increased ketogenesis was not due to an increase in enzymic capacity for long-chain acylcarnitine formation. Dexamethasone and BcAMP, separately and in combination, increased gluconeogenesis. In the presence of insulin, however, dexamethasone inhibited gluconeogenesis. Changes in gluconeogenesis thus paralleled changes in ketogenesis. Dexamethasone decreased the [3-hydroxybutyrate]/[acetoacetate] ratio, despite increasing the rate of ketogenesis and presumably the mitochondrial production of reducing equivalents. The more oxidized mitochondrial NADH/NAD+ redox couple with dexamethasone is probably due either to an increased rate of electron transport or to increased transfer of mitochondrial reducing equivalents to the cytoplasm.
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PMID:Regulation of ketogenesis, gluconeogenesis and the mitochondrial redox state by dexamethasone in hepatocyte monolayer cultures. 382 16

Cl- conductance of the apical membrane of airway epithelial cells has properties of a passive diffusion mechanism but is decreased by inhibition of oxidative metabolism. Recent reports that cAMP-dependent Cl- conductance also requires ATP at the intracellular domains of the cystic fibrosis transmembrane conductance regulator (CFTR) suggests that ATP concentration could mediate metabolic regulation of Cl- conductance. However, metabolic inhibitors affect processes other than ATP free energy levels, including notably the metabolic pathways that set the redox potential of pyridine nucleotides within the cell. We have investigated the possibility that CFTR-mediated Cl- conductance is affected by the ratio of oxidized to reduced intracellular pyridine nucleotides. CFTR was expressed in airway and heterologous cells and studied under whole cell voltage clamp conditions, which permitted the intracellular NAD(P)+/NAD(P)H ratio to be varied independently of ATP concentration. In three cell types expressing CFTR, whole cell dialysis with reduced pyridine nucleotides inhibited activation of Cl- currents by forskolin and 8-(4-chlorophenylthio)-cAMP (CPT-cAMP), whereas dialysis with oxidized pyridines increased both basal and stimulated CFTR-mediated Cl- conductance. In cell-attached membrane patches, the open probability of 5-6-picosiemens Cl- channels that had been activated by forskolin and CPT-cAMP was further and reversibly increased by permeant oxidants. Neither swelling-induced whole cell K+ currents in CFTR-expressing cells nor swelling-induced whole cell Cl- currents in multidrug resistance protein-expressing cells were affected by NADPH. Pyridine nucleotide redox potential had little effect on phosphorylation of histone by protein kinase A. We conclude that CFTR Cl- conductance function can be modulated by pyridine nucleotide redox potential. This effect points to the existence of a mechanism or mechanisms by which cytosolic nucleotides other than ATP can affect plasma membrane Cl- conductance and may help explain how a passive ion conductance is linked to cellular energy metabolism.
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PMID:Pyridine nucleotide redox potential modulates cystic fibrosis transmembrane conductance regulator Cl- conductance. 751 Jun 95


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