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)

In recent years the rapid regulation of acetyl-CoA (AcCoA) carboxylase (EC 6.4.1.2) has become of major interest because of the important role of malonyl-CoA in fatty acid synthesis, ketogenesis, and triglyceride production. AcCoA carboxylase is acutely regulated by two mechanisms: 1) phosphorylation-dephosphorylation and 2) polymer-protomer transition. Until recently polymer-protomer transition of AcCoA carboxylase in vivo has escaped detection. We developed a technique that estimates the intracellular proportion of polymer and protomer forms of AcCoA carboxylase based on the differential sensitivity of polymeric and protomeric AcCoA carboxylase to avidin inactivation. When the enzyme is in its highly aggregated conformation, the biotin prosthetic group of AcCoA carboxylase is protected from avidin binding. Thus the polymeric AcCoA carboxylase is more resistant than the protomeric conformation to avidin inactivation. Utilizing this technique with isolated liver cells we have been able to develop a model for the involvement of free fatty acids and glucagon in regulating polymer-protomer transition of AcCoA carboxylase, and the role of polymer as an intracellular determinant of AcCoA carboxylase activity. Our data suggest that the physiological regulation of AcCoA carboxylase involves the interaction of the phosphorylation mechanism with fatty acid-induced depolymerization. We propose that during periods of food deprivation the elevation in fatty acid-CoA esters promotes depolymerization of AcCoA carboxylase. In addition, glucagon induces phosphorylation of AcCoA carboxylase, which inhibits the enzyme's activity and facilitates acyl-CoA binding and depolymerization. The two separate mechanisms for regulating hepatic AcCoA carboxylase may work in concert to modulate the level of the regulatory metabolite malonyl-CoA.
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PMID:Fatty acid-mediated disaggregation of acetyl-CoA carboxylase in isolated liver cells. 285 22

When fasted rats were refed for 4 days with a carbohydrate and protein diet, a carbohydrate diet (without protein) or a protein diet (without carbohydrate), the effects of dietary nutrients on the fatty acid synthesis from injected tritiated water, the substrate and effector levels of lipogenic enzymes and the enzyme activities were compared in the livers. In the carbohydrate diet group, although acetyl-CoA carboxylase was much induced and citrate was much increased, the activity of acetyl-CoA carboxylase extracted with phosphatase inhibitor and activated with 0.5 mM citrate was low in comparison to the carbohydrate and protein diet group. The physiological activity of acetyl-CoA carboxylase seems to be low. In the protein diet group, the concentrations of glucose 6-phosphate, acetyl-CoA and malonyl-CoA were markedly higher than in the carbohydrate and protein group, whereas the concentrations of oxaloacetate and citrate were lower. The levels of hepatic cAMP and plasma glucagon were high. The activities of acetyl-CoA carboxylase and also fatty acid synthetase were low in the protein group. By feeding fat, the citrate level was not decreased as much as the lipogenic enzyme inductions. Comparing the substrate and effector levels with the Km and Ka values, the activities of acetyl-CoA carboxylase and fatty acid synthetase could be limited by the levels. The fatty acid synthesis from tritiated water corresponded more closely to the acetyl-CoA carboxylase activity (activated 0.5 mM citrate) than to other lipogenic enzyme activities. On the other hand, neither the activities of glucose-6-phosphate dehydrogenase and malic enzyme (even though markedly lowered by diet) nor the levels of their substrates appeared to limit fatty acid synthesis of any of the dietary groups. Thus, it is suggested that under the dietary nutrient manipulation, acetyl-CoA carboxylase activity would be the first candidate of the rate-limiting factor for fatty acid synthesis with the regulations of the enzyme quantity, the substrate and effector levels and the enzyme modification.
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PMID:Effects of dietary nutrients on substrate and effector levels of lipogenic enzymes, and lipogenesis from tritiated water in rat liver. 287 38

The capacity for gluconeogenesis in the isolated amphibian retina was found to be approx. 70-fold greater with lactate than with glutamate as the gluconeogenic precursor, 1426 versus 21 pmol of glucose incorporated into glycogen/h per mg of protein. It was also found that 11-15% of the glucosyl units in glycogen are derived from C3 metabolites of the glycolytic pathway, suggesting that lactate is recycled within the retina. In concert with these metabolic observations, a full complement of the gluconeogenic enzymes was detected in retinal homogenates. These included: glucose-6-phosphatase, fructose-1,6-bisphosphatase, acetyl-CoA-dependent pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Agents that regulate the rate of gluconeogenesis in hepatic tissue were tested on the retina. At concentrations of glutamate and lactate that are presumed to be relevant physiologically, it was found that vasoactive intestinal peptide, ionophore A23187 and elevated [K+] each enhanced the rate of gluconeogenesis in Ringer containing 50 microM-glutamate, whereas in Ringer containing 8.5 mM-lactate these agents inhibited the rate of gluconeogenesis. Further, it was found that the classic gluconeogenic hormone glucagon inhibited gluconeogenesis in both glutamate- and lactate-containing Ringer. Retinal energy metabolism was found to be altered in lactate-containing Ringer, in that lactate production was suppressed completely. In addition, glycogen metabolism appeared to be dependent on increased cytosolic Ca2+ and was insensitive to increased retinal cyclic AMP.
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PMID:Gluconeogenesis in the amphibian retina. Lactate is preferred to glutamate as the gluconeogenic precursor. 290 49

Hepatocytes were isolated from the livers of fed rats and incubated, in the presence and absence of 100 nM-glucagon, with a substrate mixture containing glucose (10 mM), fructose (4 mM), alanine (3.5 mM), acetate (1.25 mM), and ribose (1 mM). In any given incubation one substrate was labelled with 14C. Incorporation of 14C into glucose, glycogen, CO2, lactate, alanine, glutamate, lipid glycerol and fatty acids was measured after 20 and 40 min of incubation under quasi-steady-state conditions [Borowitz, Stein & Blum (1977) J. Biol. Chem. 252, 1589-1605]. These data and the measured O2 consumption were analysed with the aid of a structural metabolic model incorporating all reactions of the glycolytic, gluconeogenic, and pentose phosphate pathways, and associated mitochondrial and cytosolic reactions. A considerable excess of experimental measurements over independent flux parameters and a number of independent measurements of changes in metabolite concentrations allowed for a stringent test of the model. A satisfactory fit to the data was obtained for each condition. Significant findings included: control cells were glycogenic and glucagon-treated cells glycogenolytic during the second interval; an ordered (last in, first out) model of glycogen degradation [Devos & Hers (1979) Eur. J. Biochem. 99, 161-167] was required in order to fit the experimental data; the pentose shunt contributed approx. 15% of the carbon for gluconeogenesis in both control and glucagon-treated cells; net flux through the lower Embden-Meyerhof pathway was in the glycolytic direction except during the 20-40 min interval in glucagon-treated cells; the increased gluconeogenesis in response to glucagon was correlated with a decreased pyruvate kinase flux and lactate output; fluxes through pyruvate kinase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase were not coordinately controlled; Krebs cycle activity did not change with glucagon treatment; flux through the malic enzyme was towards pyruvate formation except for control cells during interval II; and 'futile' cycling at each of the five substrate cycles examined (including a previously undescribed cycle at acetate/acetyl-CoA) consumed about 26% of cellular ATP production in control hepatocytes and 21% in glucagon-treated cells.
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PMID:Quantitative analysis of intermediary metabolism in hepatocytes incubated in the presence and absence of glucagon with a substrate mixture containing glucose, ribose, fructose, alanine and acetate. 391 12

Ketogenesis may be controlled at several sites. Lipolysis with release of plasma nonesterified fatty acid (NEFA) substrate is the first step. Plasma NEFA are taken up by the liver in a concentration-dependent fashion and, after conversion to the acyl-CoA derivative, may either be reesterified or enter the mitochondria via the carnitine shuttle. After beta-oxidation the resultant acetyl-CoA may either be converted to ketone bodies that are then released into the circulation or be condensed with oxaloacetate and enter the tricarboxylic acid cycle, the third potential control point. In humans, infusion of epinephrine causes a transient two- to threefold increase in fatty acids, glycerol, and ketone bodies. Insulin levels show a small absolute increase. Norepinephrine has similar effects, although insulin levels tend to be suppressed and glucagon levels rise somewhat. If somatostatin is added simultaneously, the lipolytic and ketogenic effects are accentuated and prolonged. Dopamine, in a high dose, has no effect on ketone bodies alone but shows small increases in NEFA and ketone bodies in the presence of somatostatin and may play a modulatory role in ketogenesis. The ketogenic effect of catecholamines could thus be in the adipocyte or in the liver. Studies with perfused liver or hepatocytes showed only trivial effects on ketogenesis even with supraphysiological doses of catecholamines. Furthermore infusion studies in rats showed decreased rather than increased ketogenesis with no change in NEFA levels. The data suggest that a) there are species differences, and b) in humans epinephrine- and norepinephrine-induced increases in ketogenesis are secondary to increases in NEFA substrate supply.
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PMID:Mechanisms of catecholamine effects on ketogenesis. 614 93

The development of fatty acid metabolism was studied in isolated hepatocytes from newborn rats. Ketone-body production from oleate is increased 6-fold between 0 and 16 h after birth. This increase is related to an enhanced beta-oxidation rather than to a channeling of acetyl-CoA from the tricarboxylic acid cycle to ketone-body synthesis. The increase in oleate oxidation is not related to a decreased esterification rate, as the latter is already low at birth and does not decrease further. At birth, lipogenic rate is 2-3-fold lower than in fed adult rats and it decreases to undetectable values in 16 h-old rats. A 90% inhibition of lipogenesis in hepatocytes of newborn rats (0 h) by glucagon and 5-(tetradecyloxy)-2-furoic acid does not lead to an increased oxidation of non-esterified fatty acids. This suggests that the inverse relationship between lipogenesis and ketogenesis in the starved newborn rat is not responsible for the switch-on of fatty acid oxidation at birth. Moreover, ketogenesis from octanoate, a medium-chain fatty acid the oxidation of which is independent of carnitine acyltransferase, follows the same developmental pattern at birth as that from oleate.
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PMID:Development and regulation of ketogenesis in hepatocytes isolated from newborn rats. 662 64

Hepatocytes prepared from rats treated with dexamethasone for 2 or 3h and maintained in the presence of 10 microM-dexamethasone in the preparation and incubation buffers showed significantly elevated rates of gluconeogenesis compared with those prepared from control animals. Dexamethasone treatment also increased the sensitivity of the cells to glucagon and the catecholamines. Analysis of the concentrations of metabolites in the gluconeogenic pathway indicated that dexamethasone decreased the intracellular concentration of pyruvate and increased those of phosphoenolpyruvate, acetyl-CoA and citrate, suggesting a stimulation of the reaction(s) converting pyruvate into phosphoenolpyruvate. This was substantiated by analysis of the pattern of metabolites found in the mitochondrial compartment after digitonin fractionation of the cells. Inclusion of 3-mercaptopicolinate in the incubation enhanced the effect of the hormone on the distribution of metabolites. Thus, in the absence of an effect of the steroid at the level of phosphoenolpyruvate carboxykinase or pyruvate kinase, dexamethasone treatment still increased the formation of malate, aspartate and citrate from pyruvate, indicating a stimulation in the intact cell of pyruvate carboxylase. It is suggested that the stimulation of pyruvate carboxylase is a result of a general activation of mitochondrial function, with an increase in the intramitochondrial concentrations of acetyl-CoA and ATP, a decrease in glutamate and an enhanced intramitochondrial [ATP]/[ADP] ratio.
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PMID:Effect of treatment of rats with dexamethasone in vivo on gluconeogenesis and metabolite compartmentation in subsequently isolated hepatocytes. 672 48

1. Compactin, (-)-hydroxycitrate and dexamethasone gave rise to a decrease in the rate of cholesterol production in hepatocytes from fed rats by interfering with the flow of substrate into the sterol biosynthetic pathway. The cells responded to the deficit of biosynthetic sterol by increasing the activity of hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase). 2. Compactin and (-)-hydroxycitrate gave similar results in hepatocytes from rats starved for 24 h but in this case dexamethasone had no significant effect. 3. Exogenous oleate interferes with the production of carbohydrate-derived acetyl-CoA and also gives rise initially to opposing effects on the rate of sterol synthesis and HMG-CoA reductase activity. Over a longer period, however, oleate itself was capable of replacing carbohydrate as the major source of carbon for sterol synthesis. 4. The increase in HMG-CoA reductase activity observed when liver cells were incubated in the presence of compactin, (-)-hydroxycitrate or oleate could be partially reversed by the simultaneous presence of glucagon. 5. Under some physiological conditions, a deficiency of biosynthetic cholesterol or of a related precursor may lead to an increase in the activity of HMG-CoA reductase.
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PMID:The role of substrate supply in the regulation of cholesterol biosynthesis in rat hepatocytes. 687 Jul 98

Birth in most mammalian species is characterized by an abrupt change from a high carbohydrate and low fat diet to a high fat and low carbohydrate diet. As the supply of glucose from the milk is not sufficient to cover the glucose needs of several tissues (such as the brain and the red blood cells) and as liver glycogen stores are exhausted within 12 hours of delivery, the newborn rapidly becomes dependent on its capacity for efficient gluconeogenesis. Among the factors that control the appearance of gluconeogenesis in the liver of the neonate, the pancreatic hormones play a crucial role. Studies in the rat have shown that the rise in plasma glucagon and the fall in plasma insulin which occur immediately after birth are the main determinants of the appearance of liver phosphoenolpyruvate carboxykinase (GTP), the rate-limiting enzyme of glyconeogenesis in this species. However, when this enzyme has reached its adult values in the liver 12 to 24 hours after birth, other factors involved in the regulation of hepatic gluconeogenesis. In order for it to maintain a high rate of gluconeogenesis the liver of the neonate must be supplied with sufficient amounts of gluconeogenic precursors and of non-esterified fatty acids. Studies in the rat have shown that active fatty acid oxidation is necessary to support gluconeogenesis by providing essential cofactors such as acetyl-CoA and NADH. The relevance of these studies for the understanding of neonatal glucose homeostasis in man is discussed.
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PMID:Glucose homeostasis in the perinatal period: the critical role of pancreatic hormones and exogenous substrates in the rat. 691 81

1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10mug/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70+/-11% decrease in [3-hydroxybutyrate] and a 58+/-9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72+/-9% decrease in the rate of production of ketone bodies and a 57+/-8% decrease in disappearance rate as assessed by [3-(14)C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.
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PMID:A possible mechanism for the anti-ketogenic action of alanine in the rat. 700 81


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