Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. A permeabilized isolated rat liver cell preparation was developed to achieve selective permeabilization of the cell membrane to metabolites and to allow the assay of mitochondrial overt carnitine palmitoyltransferase (CPT I) activity in situ. By performing the digitonin-induced permeabilization in the presence of fluoride and bivalent-metal-cation sequestrants, it was possible to demonstrate that the activity of other enzymes, which are regulated by reversible phosphorylation, was preserved during the procedure and subsequent washing of cells before assay. 2. CPT activity at a sub-optimal palmitoyl-CoA concentration was almost totally (approximately 90%) inhibited by malonyl-CoA, indicating that mitochondrial CPT I was largely measured in this preparation. 3. The palmitoyl-CoA-saturation and malonyl-CoA-inhibition curves for CPT activity in permeabilized cells were very similar to those obtained previously for the enzyme in isolated liver mitochondria. Moreover, starvation and diabetes had the same effects on enzyme activity, affinity for palmitoyl-CoA and malonyl-CoA sensitivity of CPT I in isolated cells as found in isolated mitochondria. These physiologically induced changes persisted through the cell preparation and incubation period. 4. Neither incubation of cells with glucagon or insulin nor incubation with pyruvate and lactate before permeabilization resulted in alterations of these parameters of CPT I in isolated cells. 5. The results are discussed in relation to the temporal relationships of changes in the activity and properties of CPT I in vivo in relation to the effects of insulin and glucagon on fatty acid metabolism in vivo.
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PMID:Use of a selectively permeabilized isolated rat hepatocyte preparation to study changes in the properties of overt carnitine palmitoyltransferase activity in situ. 328 53

An assay procedure for carnitine palmitoyltransferase is described which allows rapid measurement of the overt activity of this enzyme in isolated rat hepatocytes. In a one-step procedure digitonin permeabilizes the plasma membrane and at the same time carnitine palmitoyltransferase activity is measured. The use of the present procedure shows that carnitine palmitoyltransferase activity is regulated on the short term by different types of agonists. Thus, insulin, epidermal growth factor, vasopressin and the phorbol ester PMA inhibit carnitine palmitoyltransferase activity, whereas glucagon treatment renders the enzyme more active. These changes in enzyme activity coincide with corresponding changes in the rate of fatty acid oxidation.
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PMID:Short-term regulation of carnitine palmitoyltransferase activity in isolated rat hepatocytes. 334 11

The activation of overt carnitine palmitoyltransferase activity that occurs when rat liver mitochondria are incubated at near-physiological temperatures and ionic strengths was studied for mitochondria obtained from animals in different physiological states. In all instances, it was found to be due exclusively to an increase in the catalytic capacity of the enzyme and not to an increase in affinity of the enzyme for palmitoyl-CoA. The enzyme in mitochondria from fed animals always showed a larger degree of activation than that in mitochondria from starved animals. This was the case even for mitochondria (e.g. from fed diabetic animals) in which the kinetic characteristics of carnitine palmitoyltransferase were more similar to those for the enzyme in mitochondria from starved rats. Glucagon treatment of rats before isolation of the mitochondria did not affect the characteristics either of the kinetic parameters of overt carnitine palmitoyltransferase or of its activation in vitro.
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PMID:Studies on the activation in vitro of carnitine palmitoyltransferase I in liver mitochondria from normal, diabetic and glucagon-treated rats. 360 74

The sensitivity of carnitine palmitoyltransferase to malonyl-CoA is lost when liver mitochondria are preincubated in a KCl-containing medium. This loss of sensitivity is slowed down in mitochondria from hypothyroid rats and accelerated in mitochondria from fasted and hyperthyroid rats. Glucagon seems to enhance the effect of fasting. The loss of sensitivity is significantly slowed down by 50-500 nM malonyl-CoA and accelerated by small amounts of palmitoyl-CoA in the preincubation medium.
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PMID:Carnitine palmitoyltransferase: activation and inactivation in liver mitochondria from fed, fasted, hypo- and hyperthyroid rats. 370 84

The regulatory mechanism of hepatic palmitate oxidation into ketone bodies by c-kinase has been studied in isolated hepatocytes. Glucagon and epinephrine stimulated [U-14C]palmitate oxidation to ketone bodies by 60 and 25% as early as at 1 h. The stimulatory effects were almost totally prevented by the simultaneous presence of vasopressin, phorbol 12-tetradecanoate 13-acetate (TPA), or diacylglycerol (1-oleoyl-2-acetylglycerol). When hepatocytes were treated with glucagon or epinephrine, carnitine palmitoyltransferase (CPT), a key regulatory enzyme of palmitate oxidation, was activated. This hormone-induced activation of CPT was not observed in the presence of TPA. These observations suggest that c-kinase inhibits glucagon- or epinephrine-stimulated palmitate oxidation to ketone bodies, and that this inhibition may be mediated through a covalent modification of CPT.
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PMID:A suppressive role of c-kinase for the stimulation of hepatic ketogenesis by glucagon and epinephrine. 370 11

Ketone bodies accumulate in the plasma in conditions of fasting and uncontrolled diabetes. The initiating event is a change in the molar ratio of glucagon:insulin. Insulin deficiency triggers the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. Glucagon appears to be the primary hormone involved in the induction of fatty acid oxidation and ketogenesis in the liver. It acts by acutely dropping hepatic malonyl-CoA concentrations as a consequence of inhibitory effects exerted in the glycolytic pathway and on acetyl-CoA carboxylase (EC 6.4.1.2). The fall in malonyl-CoA concentration activates carnitine acyltransferase I (EC 2.3.1.21) such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. The latter are high-capacity systems assuring that fatty acids entering the mitochondria are rapidly oxidized to ketone bodies. Thus, the rate-controlling step for ketogenesis is carnitine acyltransferase I. Administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations, increases the liver concentration of malonyl-CoA, inhibits carnitine acyltransferase I and reverses the ketogenic process.
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PMID:The regulation of ketogenesis. 612 45

1. The effect of triiodothyronine on the metabolism of palmitate, oleate and erucate in isolated rat hepatocytes was studied. 2. In triiodothyronine-treated rats increased oxidation and decreased triacylglycerol formation from palmitate and oleate was observed. For erucate triiodothyronine caused increased oxidation, but had no significant effect on esterification. 3. Glucagon had no effect on the fatty acid metabolism in hepatocytes from triiodothyronine-treated rats, whereas it stimulated the oxidation in hepatocytes from normal rats. Still, after treatment with triiodothyronine, the oxidation of fatty acids was significantly higher than in glucagon-stimulated normal hepatocytes. 4. In isolated rat liver mitochondria triiodothyronine raised the activity of the outer carnitine palmitoyltransferase (EC 2.3.1.21). The activity of the total carnitine palmitoyltransferase was elevated only slightly in isolated mitochondria from triiodothyronine-treated rats. These effects were similar to those seen in fasted rats. 5. Triiodothyronine had no significant influence on the concentration of long-chain acyl-CoA or alpha-glycerophosphate in isolated rat hepatocytes.
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PMID:The metabolism of fatty acids in hepatocytes isolated from triiodothyronine-treated rats. 706 76

We examined effects of a novel antidiabetic agent, racemic englitazone (CP 68,722, Pfizer), on normal rat hepatocytes in vitro. For optimal effects, CP 68,722 must be preincubated for approximately 20 minutes. CP 68,722 inhibited the actions of glucagon on glycogenolysis (measured by monitoring cyclic adenosine monophosphate [cAMP] levels, phosphorylase activation, and glucose output) and gluconeogenesis (from 14C-lactate). Since CP 68,722 was able to attenuate the ability of glucagon to increase cAMP levels, this may account for part of its inhibitory actions on glycogenolysis and gluconeogenesis. The observation that CP 68,722 also inhibits the ability of the cAMP analog, 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic monophosphate (8 CPT cAMP), to stimulate phosphorylase a is consistent with an effect of CP 68,722 to activate cAMP-dependent phosphodiesterase. The ability of vasopressin (an agonist known to stimulate glycogenolysis via a Ca(2+)-dependent mechanism) to stimulate phosphorylase a was slightly inhibited by CP 68,722. Another site of action of CP 68,722 was to inhibit hormonal-mediated Ca2+ influx, an effect that would decrease intracellular free calcium ([Ca2+]i), thereby inhibiting the actions of the Ca(2+)-dependent hormones such as alpha 1-adrenergic agonists and vasopressin, agents known to promote glucose output from the liver. In summary, CP 68,722 inhibits glucagon-stimulated glycogenolysis and gluconeogenesis in hepatocytes by a mechanism that may include activation of cAMP phosphodiesterase and inhibition of Ca2+ influx.
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PMID:Actions of the novel antidiabetic agent englitazone in rat hepatocytes. 824 73

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

Addition of 8-bromo-adenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) or 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (8-CPT-cAMP) to hepatocytes at the time of plating enhanced the acquisition of beta-adrenoceptors that occurs spontaneously upon culturing as primary monolayers. This effect was partially suppressed by the phosphodiesterase inhibitor isobutyl methylxanthine, and was mimicked by 8-bromo-AMP, 8-bromo-adenosine, and the adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine. Agents that elevated the intracellular level of cAMP, such as glucagon and forskolin, and Sp-8-bromo-adenosine 3',5'-monophosphorothioate (Sp-8-bromo-cAMPS), a cAMP analogue that is resistant towards metabolic breakdown, did not significantly enhance beta-adrenoceptor expression when used alone, but glucagon enhanced the effect of 8-bromo-adenosine. 8-bromo-cAMP and 8-bromo-adenosine decreased cellular ATP-levels. These observations suggest that the enhanced beta-adrenoceptor acquisition was mediated mainly through the action of metabolites of 8-bromo-cAMP and 8-CPT-cAMP, although there may be a cAMP-mediated component in the effect. Several mechanisms, including depletion of ATP, are probably involved, and might affect beta-adrenoceptor degradation.
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PMID:8-bromo-cAMP and 8-CPT-cAMP increase the density of beta-adrenoceptors in hepatocytes by a mechanism not mimicking the effect of cAMP. 884 Oct 91


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