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)

The review examines the mechanisms regulating the activities of the two key enzymes determining rates of glucose and fatty acid oxidation, i.e., the pyruvate dehydrogenase (PDH) complex and the carnitine palmitoyltransferase (CPT) system. The review also evaluates the regulatory importance of gene expression in the control of tissue fuel selection within the context of substrate competition between glucose and fatty acids. It identifies a strong indirect input of nutrient-gene interactions in the control of pyruvate oxidation through the regulated provision of pyruvate as a substrate for PDH and as an inhibitor of PDH kinase. Nutrient-gene interactions are also identified in relation to the regulation of CPT I activity by malonyl-CoA (inhibitor) and by the provision of long-chain acyl-CoA (substrate/activator), the latter via the hydrolysis of plasma or tissue triacylglycerol (by lipoprotein lipase and hormone-sensitive lipase, respectively). We discuss how such regulation is reinforced by long-term modulation of PDH kinase-specific activity and CPT I maximal activity. We also explore the role of mechanisms operating at the levels of the PDH complex and the CPT system that act to promote and accelerate a switch in fuel utilization once a committed change in nutrient supply has been established. In particular, we discuss the regulatory influences exerted by altered sensitivities of PDH kinase to inhibition by pyruvate and CPT I to inhibition by malonyl-CoA, respectively.
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PMID:Interactive regulation of the pyruvate dehydrogenase complex and the carnitine palmitoyltransferase system. 829 90

This study was designed to determine the effects of glucose and insulin on malonyl-CoA, the potent inhibitor of carnitine palmitoyltransferase I, in the gastrocnemius/plantaris muscle group. Isolated rat hindlimbs were perfused with Krebs-Henseleit bicarbonate buffer containing fresh erythrocytes (hematocrit = 41) and albumin in a flow-through mode for 60 min. Two experiments were performed. In the first, hindlimbs were perfused with medium containing no glucose and no insulin (n = 9) or with medium containing 10 mM glucose and 100 microU/ml of insulin (n = 9). Gastrocnemius/plantaris malonyl-CoA was 0.6 +/- 0.1 nmol/g in the absence of glucose and insulin vs. 1.4 +/- 0.1 nmol/g when both glucose and insulin were added. In the second experiment, hindlimbs were perfused with medium containing 10 mM glucose alone, 200 microU insulin alone, or with a combination of 10 mM glucose and 200 microU/ml of insulin (n = 8 for each). Malonyl-CoA was decreased in gastrocnemius/plantaris perfused with glucose alone (0.7 +/- 0.2 nmol/g) and with insulin alone (0.7 +/- 0.1 nmol/g) compared with hindlimbs perfused with the combination of glucose and insulin (1.4 +/- 0.2 nmol/g). We conclude that both glucose and insulin are required for preventing a decline in muscle malonyl-CoA.
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PMID:Control of malonyl-CoA by glucose and insulin in perfused skeletal muscle. 833 89

The purpose of these studies was to quantify several mRNAs expressed specifically in pancreatic islet cells and known or postulated to be important for insulin release after acute well defined alterations in levels of plasma glucose. Glucose levels were maintained at 50, 120, or 180 mg/dl (2.8, 6.7, or 10 mM) for 3 h in conscious unrestrained rats. Hypoglycemia (for 3 h) caused significant decreases in pancreatic content of mRNAs for insulin 2 and GLUT-2 to 55 and 34% of control values, respectively. There were no significant changes in insulin 1, amylin, glucokinase, or glucagon mRNAs. Unprocessed insulin 1 and 2 mRNA precursors were decreased to 17 and 10% of levels in controls, consistent with effects of short-term hypoglycemia on new mRNA synthesis. Hyperglycemia (for 3 h) caused no increase in pancreatic content of any mRNA measured. To discriminate between effects of hypoglycemia and hyperinsulinemia in the hypoglycemic animals, rats were made hypoglycemic by infusion with etomoxir, a carnitine palmitoyltransferase I inhibitor that lowers glucose in the fasted (glycogen-depleted) state by inhibiting hepatic gluconeogenesis. A single dose of this agent caused a decrease in glucose from 120 mg/dl (6.7 mM) to 80 mg/dl (4.4 mM) and significantly decreased insulin mRNA and pre-mRNA. These results are consistent with the hypothesis that glucose modulates islet cell gene transcription directly. They indicate that the range of glucose concentrations that modulate gene transcription differs from the levels of glucose that alter both insulin biosynthetic and secretion rates.
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PMID:Hypoglycemia but not hyperglycemia induces rapid changes in pancreatic beta-cell gene transcription. 836 95

Facilitated transport of urea by the inner medullary collecting duct in kidney is important for the urinary concentrating mechanism. To examine the nature and tissue distribution of urea transporters, mRNA was isolated from different tissues and expressed in Xenopus oocytes. [14C]urea and [3H]methylglucose uptake were measured at 21 degrees C at 64 h after microinjection of mRNA. Relative urea uptake in oocytes injected with 50 ng of unfractionated mRNA was (n = 6-42): 1.0 (water-injected control), 1.0 +/- 0.3 (human kidney cortex), 2.9 +/- 0.5 (rat kidney papilla), 2.5 +/- 0.5 (human kidney papilla), 2.7 +/- 0.3 (rat liver), 1.1 +/- 0.3 (rat brain), 1.2 +/- 0.3 (rat muscle), and 2.6 +/- 0.3 (rabbit reticulocyte). Urea uptake was inhibited to near control values by 0.2 mM phloretin and 0.2 mM p-chloromercuribenzenesulfonate (pCMBS) in oocytes injected with mRNA from kidney medulla, liver, and reticulocyte; phloretin and pCMBS had no effect in control oocytes and oocytes injected with mRNA from kidney cortex, brain, and muscle. Urea uptake was strongly increased in oocytes injected with kidney medulla mRNA (4.4-fold over control) by a 5-min preincubation with the adenosine 3',5'-cyclic monophosphate (cAMP) agonist adenosine-3',5'-cyclic monophosphorothioate (Sp-cAMPS) or a mixture of CPT-cAMP, forskolin, and 3-isobutyl-1-methylxanthine; cAMP agonists did not affect urea uptake in oocytes expressing the reticulocyte and liver urea transporters. As an internal control, (phloretin inhibitable) glucose uptake was enhanced in all oocytes (up to 5-fold greater than control), and was not affected by pCMBS and the cAMP agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional expression of cAMP-dependent and independent urea transporters in Xenopus oocytes. 839 30

To examine the influence of elevated free fatty acid (FFA) levels on hepatic glucose production (HGP) and oxidative and nonoxidative pathways of glucose metabolism, 12 healthy subjects participated in two euglycemic insulin-clamp studies performed with and without infusion of Intralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measurement of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid plus heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhibited by insulin. Suppression of HGP by insulin was impaired by elevated plasma FFA levels. Furthermore, the increase in plasma FFA was associated with a 20% reduction in total glucose metabolism (P < 0.01), which was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by insulin, elevation of plasma FFA had no influence on this key enzyme of glycogen synthesis. In addition, the activities of PDH and CPT were uninfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose-fatty acid cycle under the current conditions. Taken together, the data indicate that the interaction between FFA and glucose metabolism also involves impaired suppression of HGP by insulin.
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PMID:Contribution of muscle and liver to glucose-fatty acid cycle in humans. 847 39

The glucose-free fatty acid (FFA) cycle (Randle) was examined in soleus muscle, a red muscle with a high lipid oxidation rate, and extensor digitorum longus (EDL) muscle, a white muscle with a low lipid oxidation rate, using a carnitine palmethyltransferase (CPT-I) inhibitor as a probe. Exogenous palmitate by itself had little if any effect on glycolysis or glycogen accumulation in the two muscle types. The CPT-I inhibitor markedly decreased glycogen accumulation in both muscles (from fed rats), but increased glycolysis (lactate formation) and glucose oxidation to carbon dioxide only in the red muscle. When the muscles were made more dependent on FFA oxidation by prior fasting or exercise, the CPT-I stimulatory effect on glycolysis and glucose oxidation in white muscle was unmasked. In conclusion, the competition between lipid and carbohydrate utilization (Randle cycle) is easily demonstrated in both red and white muscle using a CPT-I inhibitor as a probe. The difficulties encountered in showing this competition in other studies using exogenous FFA may be explained by a combination of factors, including (1) low tissue lipid oxidation rates, (2) competition between exogenous and endogenous lipids such that provision of exogenous lipids fails to increase overall lipid oxidation, and (3) preferential utilization of exogenous glucose with glycogen sparing in the presence of FFA.
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PMID:Skeletal muscle lipids and glycogen mask substrate competition (Randle cycle). 848 67

A typical clinical feature of patients with fasting hyperglycemia in diabetes is well correlated with accelerated hepatic glucose production which is determined by elevated FFA-induced gluconeogenesis. Therefore, to treat fasting hyperglycemia, inhibition of both FFA release and fatty acid oxidation in the liver may be efficient modalities of treatment. (1) Inhibitor of FFA release: a novel selective adenosine A1 agonist, SDZ WAG 994 is a potent inhibitor of adenosine deaminase-induced lipolysis. Twenty-three-week old, male GK rats showing glucose intolerance were treated with WAG 994 (1000 micrograms/kg body weight) for 16 days. Plasma glucose level at 0 time in WAG group was significantly (P < 0.01) less than that of the control. Both plasma FFA and triglyceride concentrations also decreased by 54% and 74%, respectively (vs. control GK rats). (2) Inhibition of hepatic fatty acid oxidation: beta-aminobetaine (emeriamine) is a water-soluble carnitine analog and inhibition of CPT-1 in isolated hepatocytes is 100 times more sensitive than that in isolated cardiocytes and it suppresses both gluconeogenesis and ketogenesis by 60-80%. However, it may be possible that this drug may induce fat deposition in the liver. An inhibitor of elevated fatty acid release from adipose tissue in concomitant with liver-specific and reversible inhibition of fatty acid oxidation may be an effective agent with hypoglycemic and hypolipidemic action for the treatment of diabetes mellitus.
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PMID:Rationale and hurdles of inhibitors of hepatic gluconeogenesis in treatment of diabetes mellitus. 852 14

We examined the effect of two novel phenylglycine derivative drugs on excitotoxicity in murine cortical cell cultures: S-4-carboxy-3-hydroxy-phenylglycine (4C3HPG), a selective agonist of mGluRs 2/3 and an antagonist at mGluRs 1/5, and S-3 hydroxy-phenylglycine (3HPG), an agonist of mGluRs 1/5. 4C3HPG attenuated slowly-triggered NMDA-induced excitotoxic neuronal death, as well as the death induced by combined oxygen-glucose deprivation, but did not affect slowly-triggered excitotoxicity induced by AMPA or kainate. As expected, 4C3HPG also reduced NMDA-induced increases in cAMP in near-pure neuronal cultures, and the protective effect of 4C3HPG on NMDA toxicity could be reversed by adding 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic-monophosphate (CPT cAMP) to the exposure medium. In contrast, 3HPG did not did not have any protective effects in these paradigms; in fact, slowly-triggered NMDA-induced excitotoxicity and the neuronal cell death induced by oxygen-glucose deprivation were potentiated. These results are consistent with the idea that the "inhibitory" mGluRs 2/3 exert a negative modulatory action on NMDA receptor-mediated excitotoxicity via reduction in neuronal cAMP levels.
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PMID:The inhibitory mGluR agonist, S-4-carboxy-3-hydroxy-phenylglycine selectively attenuates NMDA neurotoxicity and oxygen-glucose deprivation-induced neuronal death. 853 57

Many authors agree that alteration of the energy substrate from glucose to free fatty acid occurs during the early stage after partial hepatectomy. An accelerative effect of carnitine on the early phase of liver regeneration was suggested in several reports, but much controversy prevails. Using male Wistar rats weighing about 200 g as subjects, we undertook partial hepatectomy with resection of the median and left lateral lobes (67%). Another group of rats undergoing a sham operation was compared. Rats were killed at 6, 24, 48, or 72 hr after the operation. The rate of synthesis of DNA and content of DNA in remnant liver were chosen as regenerative indicators. Serum carnitine, free fatty acid and its metabolites, remnant liver carnitine palmitoyltransferase I (CPT-I) activity, high-energy phosphate (HEP), including adenosine triphosphate (ATP), and creatine phosphate (CP) were measured. The results showed a marked decrease of HEP, ATP, and CP with suddenly increased free fatty acid and total ketone body in serum that occurred during the early regenerating phase after partial hepatectomy. Serum L-carnitine also increased markedly in this early stage. The mitochondrial CPT-I activity in the remnant liver decreased significantly 24 hr after partial hepatectomy. Our data show that regenerating liver utilizes free fatty acids as an immediate main substrate. Mitochondrial respiration with a CPT-I effect could be an important reaction in this utilization.
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PMID:Alterations of remnant liver carnitine palmitoyltransferase I activity and serum carnitine concentration after partial hepatectomy in rats. 853 77

We studied the effects of fatty acid oxidation on insulin secretion of db/db mice and underlying molecular mechanisms of these effects. At 2-3 months of age, db/db mice were markedly obese, hyperglycemic, and hyperinsulinemic. Serum free fatty acid (FFA) levels were increased in 2-month-old (1.5 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05) and 3-month-old (1.9 +/- 0.1 vs. 1.2 +/- 0.1 mmol/l, P < 0.01) mice compared with the age and sex-matched db/+ mice serving as controls. Glucose-induced insulin release from db/db islets was markedly decreased compared with that from db/+ islets and was specifically ameliorated (by 54% in 2-month-old and 38% in 3-month-old mice) by exposure to a carnitine palmitoyltransferase I inhibitor, etomoxir (1 micromol/l). Etomoxir failed to affect the insulin response to alpha-ketoisocaproate. The effect of etomoxir on glucose-induced insulin release was lost after culturing db/db islets in RPMI medium containing 22 mmol/l glucose but no fatty acid. Culture of db/+ islets with 0.125 mmol/l palmitate led to a decrease in glucose-induced insulin secretion, which was partially reversible by etomoxir. Both islet glucose oxidation and the ratio of glucose oxidation to utilization were decreased in db/db islets. Etomoxir significantly enhanced glucose oxidation by 60% and also the ratio of oxidation to glucose utilization (from 27 +/- 2.5 to 37 +/-3.0%, P < 0.05). Pyruvate dehydrogenase (PDH) activity was decreased in islets of db/db mice (75 +/-4.2 vs. 91 +/- 2.9 nU/ng DNA, P < 0.01), whereas PDH kinase activity was increased (rate of PDH inactivation -0.25 +/- 0.02 vs. - 0.11 +/- 0.02/min, P < 0.0 1). These abnormalities were partly but not wholly reversed by a 2-h preexposure to etomoxir. In conclusion, elevated FFA levels in the db/db mouse diminish glucose-induced insulin secretion by a glucose-fatty acid cycle in which fatty acid oxidation inhibits glucose oxidation by decreasing PDH activity and increasing PDH kinase activities.
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PMID:A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse. 862 Oct 7


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