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)

Fatty acid metabolism was studied in periportal and perivenous hepatocytes isolated by the method of Chen & Katz [Biochem. J. (1988) 255, 99-104]. The rate of fatty acid synthesis and the activity of acetyl-CoA carboxylase were markedly enhanced in perivenous hepatocytes as compared with periportal cells. However, the response of these two parameters to short-term modulation by cellular effectors such as the hormones insulin and glucagon, the phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate and the xenobiotics ethanol and acetaldehyde was similar in the two zones of the liver. In addition, perivenous hepatocytes showed a higher capacity of esterification of exogenous fatty acids into both cellular and very-low-density-lipoprotein lipids. Nevertheless, no difference between the two cell sub-populations seemed to exist in relation to the secretion of very-low-density lipoproteins. On the other hand, the rate of fatty acid oxidation was increased in periportal cells. This could be accounted for by a higher activity of carnitine palmitoyltransferase I and a lower sensitivity of this enzyme to inhibition by malonyl-CoA in the periportal zone. No differences were observed between periportal and perivenous hepatocytes in relation to the short-term response of fatty acid oxidation and carnitine palmitoyltransferase I activity to the cellular modulators mentioned above. In conclusion, our results show that: (i) lipogenesis is achieved at higher rates in the perivenous zone of the liver, whereas the fatty-acid-oxidative process occurs with a certain preference in the periportal area of this organ; (ii) the short-term response of the different fatty-acid-metabolizing pathways to cellular effectors is quantitatively similar in the two zones of the liver.
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PMID:Zonation of fatty acid metabolism in rat liver. 257 74

Insulin treatment of streptozotocin-diabetic rats restores the depressed palmitoyl-group oxidation observed in brown-adipose-tissue mitochondria from diabetic rats. A relatively rapid effect of insulin (5 h) to increase carnitine-dependent oxidation of palmitoyl-CoA and to increase overt carnitine palmitoyltransferase activity is differentiated from a slower effect of the hormone (1 day) to increase palmitoylcarnitine oxidation.
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PMID:Differentiation of rapid and slower-acting effects of insulin on mitochondrial processes in brown adipose tissue from streptozotocin-diabetic rats. 264 91

Drugs to treat diabetes that can be taken orally have long been sought, although the successful management of insulin-dependent diabetes mellitus by simple chemotherapy may be an unachievable goal. The only drugs currently used for the treatment of non-insulin-dependent diabetes have limited effectiveness. In this article Peter Selby and Stanley Sherratt describe the development of a new group of candidate hypoglycaemic drugs, esters of substituted 2-oxiranecarboxylic acids, which merit full clinical evaluation. These drugs are hydrolysed to the free acids which are then converted to their coenzyme A esters in cells. The CoA esters inactivate carnitine palmitoyltransferase I in the outer mitochondrial membrane, thus preventing the excessive oxidation of long-chain fatty acids that occurs in diabetes. This causes a secondary decrease in hepatic gluconeogenesis and an increase in peripheral glucose utilization leading to improved glucose tolerance.
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PMID:Substituted 2-oxiranecarboxylic acids: a new group of candidate hypoglycaemic drugs. 269 42

The effect of insulin on the abundance of mRNAs coding for tyrosine aminotransferase (TAT; EC 2.6.1.5), tryptophan oxygenase (TO; EC 1.13.1.12), and P-enolpyruvate carboxykinase(GTP) (PEPCK; EC 4.1.1.32) was examined in primary cultures of adult rat hepatocytes and in FTO-2B rat hepatoma cells by Northern blot analysis using RNA probes made from SP6-cDNAs. Insulin (10(-11)-10(-7) M), which has been reported to induce TAT and decrease the activity of TO, did not change the levels of TAT mRNA and TO mRNA in hepatocytes regardless of the presence of other inducers. In the same cells, dexamethasone increased TAT mRNA up to 19-fold and TO mRNA up to 15-fold, and 8pClPhS-cAMP (CPT-cAMP) raised the level of TAT mRNA up to 36-fold. The abundance of TO mRNA was not altered by CPT-cAMP. In contrast to TAT mRNA and TO mRNA, the level of PEPCK mRNA was dramatically decreased by insulin in the same hepatocytes. The sensitivity to this inhibitory effect of insulin was enhanced by dexamethasone and reduced by CPT-cAMP. FTO-2B hepatoma cells, which do not express detectable levels of TO mRNA, showed responses similar to those of hepatocytes, except that insulin caused a moderate reduction in TAT mRNA, but only in the presence of CPT-cAMP. The PEPCK mRNA in FTO-2B cells was suppressed by insulin in a manner closely resembling the effects in hepatocytes in the present study and in H4IIE hepatoma cells previously reported.
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PMID:Regulation of gene expression in rat hepatocytes and hepatoma cells by insulin: quantitation of messenger ribonucleic acid's coding for tyrosine aminotransferase, tryptophan oxygenase, and phosphoenolpyruvate carboxykinase. 287 68

The long-term regulation of hepatic mitochondrial carnitine palmitoyltransferase (CPT) was studied in control, insulin-treated, and untreated spontaneously diabetic BB Wistar rats. The activity of CPT was elevated approximately twofold in the untreated diabetic rats. This corresponded to an approximately equivalent elevation in the immunoreactive CPT activity. mRNACPT was assayed by reticulocyte lysate translation and by dot blot to a CPT oligonucleotide probe. The level of mRNACPT was approximately proportional to the observed CPT activity. A cDNA probe to CPT was developed, and transcriptional activity for CPT was assessed in isolated hepatic nuclei. Again, transcription of CPT mRNA was approximately proportional to the observed activity. We therefore conclude that at least part of the long-term regulation of hepatic CPT in spontaneously diabetic BB Wistar rats is the product of increased de novo synthesis of CPT protein brought about by regulation at the transcriptional level. Additional control of the amount of CPT may be via the regulation of RNA processing and turnover and enzyme insertion into the mitochondrial membrane.
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PMID:Regulation of carnitine palmitoyltransferase synthesis in spontaneously diabetic BB Wistar rats. 290 13

Administration to normal rats of 100 mg of streptozotocin/kg body weight produced ketotic diabetic rats in which the affinity of carnitine palmitoyltransferase for malonyl-CoA was decreased by 10-fold and its activity was increased by 30%, but the injection of insulin brought the affinity and the activity back to normal within 4 h. Administration of 60 mg of streptozotocin/kg produced non-ketotic diabetic rats and caused a less substantial change in the affinity of carnitine palmitoyltransferase for malonyl-CoA. In the BB Wistar diabetic rat, the onset of diabetes also increased the activity of carnitine palmitoyltransferase and decreased its affinity for malonyl-CoA. Injection of insulin brought both of these values back to normal within 2 h. The total activity of mitochondrial carnitine palmitoyltransferase (outer + inner activities) was 40% greater in the BB Wistar diabetic rat, but treatment with insulin did not decrease the total activity to normal values within 2 h. The elevated activity and decreased affinity for malonyl-CoA found in fasting rats did not respond to short-term insulin treatment. The evaluation of a previous report that cycloheximide blocks the effects of starvation indicated that cycloheximide did not act by inhibiting protein synthesis, but produced its effect by preventing gastric emptying. Current data suggest that diabetes increases the activity of carnitine palmitoyltransferase and greatly diminishes the affinity of the enzyme for malonyl-CoA and that the severity of diabetes is associated with differences in the affinity of the enzyme for its inhibitor. Insulin acts on the outer carnitine palmitoyltransferase to reverse these effects very rapidly, but diabetes produces some change in the total activity that is not reversed by short-term treatment with insulin.
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PMID:Regulation of carnitine palmitoyltransferase by insulin results in decreased activity and decreased apparent Ki values for malonyl-CoA. 295 85

In the anterogradely perfused rat heart with glucose as fuel, 1 microM isoproterenol (ISO) inhibited the insulin (INS) plus adenosine deaminase (AdoDA) stimulation of ventricular protein synthesis by 72%. ISO (1 microM) alone had no effect on ventricular protein synthesis but inhibited atrial protein synthesis by 20%. The concentration dependence of the ISO inhibition was similar to the stimulation of glucose uptake by ISO. Inhibition could not be overcome by increasing INS concentrations. The effects of ISO were diminished by propranolol and could be partially mimicked by forskolin (FSK) or 8-(4-chlorophenylthio-)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). The stimulation of protein synthesis by noncarbohydrate fuels was antagonized by ISO. Hypoxia (PO2 = 50%) also antagonized the INS stimulation of ventricular protein synthesis but did not affect basal rates. ATP contents were decreased by ISO but not by a PO2 of 50%. Both manipulations increased lactate output. The inhibition of protein synthesis by ISO could possibly be explained by indirect effects of ISO on cardiac "energy status." Furthermore, inhibition may thus represent purely an in vitro phenomenon and may not occur in vivo. However, the possibility that there are more direct effects of ISO on the machinery of protein synthesis has not been excluded. The inhibition of protein synthesis by hypoxia cannot be explained by changes in energy status and may result from intracellular lactoacidosis.
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PMID:Acute inhibition of rat heart protein synthesis in vitro during beta-adrenergic stimulation or hypoxia. 305 5

The effects of ethanol administration on activity and regulation of carnitine palmitoyltransferase I (CPT-I) were studied in hepatocytes isolated from rats fed a liquid, high-fat diet containing 36% of total calories as ethanol or an isocaloric amount of sucrose. Cells were isolated at several time points in the course of a 5-week experimental period. Ethanol consumption markedly decreased CPT-I activity and increased enzyme sensitivity to inhibition by exogenously added malonyl-CoA. Changes in enzyme activity occurred sooner than those in enzyme sensitivity. Fatty acid oxidation to CO2 and ketone bodies was depressed in hepatocytes from ethanol-fed animals during the first part of the treatment. At the end of the 35-day period, there were no longer differences in the rate of ketogenesis between the two groups. At that time, however, the rate of CO2 formation was still impaired in the ethanol-fed animals. Furthermore, addition of ethanol or acetaldehyde to the incubation medium strongly depressed CPT-I activity and rates of fatty acid oxidation in hepatocytes from ethanol-treated rats, whereas these effects were much less pronounced in cells from control animals. The response of CPT-I activity to insulin, glucagon, vasopressin, and phorbol ester was blunted in cells derived from ethanol-fed rats. These changes in the regulation of CPT-I activity corresponded with those observed in the rate of fatty acid oxidation. It is concluded that CPT-I may play a role in the generation of the ethanol-induced fatty liver.
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PMID:Effects of ethanol feeding on the activity and regulation of hepatic carnitine palmitoyltransferase I. 306 12

1. The kinetic properties of overt carnitine palmitoyltransferase (CPT I, EC 2.3.1.21) were studied in rat liver mitochondria isolated from untreated, diabetic and insulin-treated diabetic animals. A comparison was made of the time courses required for the changes in these properties of CPT I to occur and for the development of ketosis during the induction of chronic diabetes and its reversal by insulin treatment. 2. The development of hyperketonaemia over the first 5 days of insulin withdrawal from streptozotocin-treated rats was accompanied by parallel increases in the activity of CPT I and in the I0.5 (concentration required to produce 50% inhibition) of the enzyme for malonyl-CoA. 3. The rapid reversal of the ketotic state by treatment of chronically diabetic rats with 6 units of regular insulin was not accompanied by any change in the properties of CPT I over the first 4 h. Higher doses of insulin (15 units), delivered throughout a 4 h period, resulted in an increase in the affinity of CPT I for malonyl-CoA, but the sensitivity of the enzyme to the inhibitor was still significantly lower than in mitochondria from normal animals. 4. Conversely, when insulin treatment was continued over a 24 h period, full restoration of the sensitivity of the enzyme to malonyl-CoA was achieved. However, the activity of the enzyme was only decreased marginally. 5. These results are discussed in terms of the possibility that the major regulatory sites of the rate of hepatic oxidation may vary in different phases of the induction and reversal of chronic diabetes.
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PMID:Role of carnitine palmitoyltransferase I in the regulation of hepatic ketogenesis during the onset and reversal of chronic diabetes. 327 23

The metabolic consequences of a prolonged gestation (35 vs 32 days) have been studied in the rabbit fetus. Gestation was prolonged by daily subcutaneous injections of progesterone (1.5 mg.kg-1) from day 28 to 34. In control animals, progesterone was injected from day 25 or 28 to day 31 of gestation. When the capacities for gluconeogenesis and fatty acid oxidation, measured on isolated hepatocytes, are normally low in the term control fetus and increase only within the first 24 h after birth, these capacities appear high in the postmature fetus. The rate of glucose production from lactate is 4-fold higher in the postmature fetus than in the normal term fetus. The rate of ketone body production from oleate is also 5-fold higher in the postmature fetus, which results from a switch on of the partition of oleate into esterification and oxidation: 8% of [1-14C]oleate is oxidized in term fetus hepatocytes, but 34% in postmature fetus hepatocytes. As a similar rate of lipogenesis takes place in both stages, this metabolic change could be explained by a 5-fold lower sensitivity of carnitine palmitoyltransferase I to the inhibition by malonyl-coenzyme A. Postmaturity decreases plasma insulin concentrations by 45% and increases plasma glucagon concentrations by 50% which, in turn, induces a 3-fold decrease in the plasma insulin:glucagon molar ratio. As previously shown in fasted or diabetic adult rat, this hormonal change might be a likely candidate for an enhancement of gluconeogenic and ketogenic capacity in the liver of the postterm rabbit fetus.
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PMID:Premature appearance of gluconeogenesis and fatty acid oxidation in the liver of the postterm rabbit fetus. 328 Nov 21


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