The Role of Endogenous Lipid in Gluconeogenesis and Ketogenesis of Perfused Rat Liver

Menahan, Lawrence A.; Wieland, O.

doi:10.1111/j.1432-1033.1969.tb00593.x

Cited by 75 publications

(53 citation statements)

References 39 publications

(36 reference statements)

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“…Since the rate of gluconeogenesis is decreased in hypothyroidism, this profile may be interpreted as indicating regulation at the fructose bisphosphatase/phosphofructokinase couple. Calculations of the intracellular distribution of nfetabolites suggest that the mitochondrial content of malate is very significantly decreased, a change which is in keeping with the reported decline of pyruvate carboxylase [6,7].…”

Section: The 'Pyruvate Csossroads' Und Gluconeogenesis In Liversupporting

confidence: 77%

“…the form of hexokinase known to be sensitive to insulin in this tissue [63]. The changes in the rate of urea formation and the activity of urea cycle enzymes in the livers of hypothyroid rats are also closely similar to those found in alloxandiabetic animals [6,64] (McLean and Brown,unpublished observations).…”

Section: Hjyothyroidisrn Cyclic Nucleotides Hepatic Metabolites Andmentioning

confidence: 55%

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Effects of Thyroid Hormone Deficiency on the Distribution of Hepatic Metabolites and Control of Pathways of Carbohydrate Metabolism in Liver and Adipose Tissue of the Rat

Baquer

Cascales

McLean

et al. 1976

European Journal of Biochemistry

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1. Measurements-have been made of the hepatic metabolites in normal and thyroidectomized rats and of enzymes of the glycolytic route, the pentose phosphate pathway, the tricarboxylic acid cycle and of lipogenesis together with the flux of glucose through alternative pathways of glucose metabolism and into lipid.2. There is 11 significant fall in the content of ADP, AMP, citrate, long-chain acyl-CoA derivatives and a h e of 3-phosphoglycerate, 2-phosphoglycerate and phosphoenolpyruvate following thyroidecto. Iy. The observed changes in the glycolytic intermediates may be correlated with the increased acLivity of phosphofructokinase relative to pyruvate kinase and fructose bisphosphatase.3. The NAD+/NADH quotient of the mitochondrial compartment, calculated from the reactants and Keq of 3-hydi-oxybutyrate dehydrogenase, becomes significantly more oxidized in hypothyroid animals. The redox state of the cytosolic NAD and NADP couples remains relatively unchanged.4. The changes in the hepatic content of CoA derivatives and citrate and in the mitochondrial redox state are interpreted as indicating a depressed rate of lipid oxidation.5. Calculations of the compartmentation of metabolites between the cytosol and mitochondria indicate a very marked decrease in mitochondria1 citrate, 2-oxoglutarate and glutamate with smaller' changes in aspartate and malate. These changes are interpreted as providing evidence for the importance of modifications in the malate-aspartate shuttle in hypothyroidism; this is further supported by measured changes in the distribution and activities of the component enzymes of the hydrogen shuttles.6. There is a diminished activity of glucokinase and of enzymes of the glycolytic pathway below phosphofructokinase in livers from hypothyroid rats. The oxidative enzymes of the pentose phosphate pathway, ATP-citrate lyase, 'malic' enzyme and fatty acid synthetase also decrease markedly. There is a striking parallelism between the changes of enzyme profile of liver and adipose tissue in hypothyroidism.7. Adrenal glands from hypothyroid rats showed a generalized decline in enzyme activity in parallel with the fall in tissue weight. Cytosolic glycerol-3-phosphate dehydrogenase decreased sharply.8. The present results are discussed in relation to data in the literature on the increased activities of cyclic AMP and cyclic GMP phosphodiesterases in hypothyroidism, observations which integrate the relationships between anabolic and catabolic pathways of carbohydrate and lipid metabolism with alterations in hormone sensitivity in hypothyroidism. E~~~~~ Commission code numbers are given in cyclic GMP, guanosine 3' : 5'-monophosphate.Tahle4.

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Section: The 'Pyruvate Csossroads' Und Gluconeogenesis In Liversupporting

confidence: 77%

Section: Hjyothyroidisrn Cyclic Nucleotides Hepatic Metabolites Andmentioning

confidence: 55%

Effects of Thyroid Hormone Deficiency on the Distribution of Hepatic Metabolites and Control of Pathways of Carbohydrate Metabolism in Liver and Adipose Tissue of the Rat

Baquer

Cascales

McLean

et al. 1976

European Journal of Biochemistry

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“…Rat Liver in the Presence of Glycodiazine and Bu2Ado-3' : 5'-P As in our previous studies with glycodiazine [24], a lipolytic inhibitor, marked inhibition of gluconeogenesis resulted (Table 2). Although pyruvate disappearance was not altered by glycodiazine, there was an increased conversion of pyruvate to lactate.…”

Section: Metabolism Of Pyruvate By the Perfusedsupporting

confidence: 76%

Interrelationship between Fatty Acid Oxidation and Gluconeogenesis from Pyruvate

Menahan¹,

Williams²

1971

European Journal of Biochemistry

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1. Both glucagon (93 nM) and N8,O2'-dibutyryl cyclic adenosine 3' : 5'-phosphate (Bu,Ado-3' : 5'-P) (10 pM) stimulated gluconeogenesis from pyruvate to the extent of 35 in the perfused liver from fasted rats. Under these conditions, all of the pyruvate disappearance could be accounted for in lactate and glucose. When livers were perfused with pyruvate only, a portion of the pyruvate metabolized was unaccounted for, and presumably oxidized.2. Bu,Ado-3' : 5'-P, even in the presence of glycodiazine, stimulated gluconeogenesis from pyruvate and lowered the ratio of C, uptake to glucose ratio, suggesting a "sparing effect" on pyruvate oxidation.3. (+)-Decanoylcarnitine (0.5 mM) blocked a significant portion of the stimulation of gluconeogenesis by glucagon (93 nM). Other parameters of pyruvate metabolism were unaltered by the carnitine ester in the presence of glucagon. I n contrast, Bu,Ado-3' : 5'-P (10 pM) in the presence of ( + )-decanoylcarnitine significantly increased glucose formation in comparison to livers perfused only with the carnitine derivative. 4. Pentenoic acid (1 .O mM) resulted in a 50°/, inhibition of gluconeogenesis, a lowered pyruvate disappearance and an increase of pyruvate unaccounted for and presumably oxidized. Livers perfused with 4-pentenoic acid in addition to glucagon exhibited a marked suppression of gluconeogenesis, a decreased conversion of pyruvate to lactate and a lowered pyruvate disappearance rate. 5. Livers perfused with Bu,Ado-3' : 5'-P (10 pM) in addition to 4-pentenoic acid, when compared to livers perfused with 4-pentenoic acid, exhibited a significantly increased rate of gluconeogenesis. Bu,-Ado-3' : 5'-P exerted a "sparing effect" on pyruvate carbon even in the presence of 4-pentenoic acid.Although the mechanism of action of fatty acid on gluconeogenesis is not yet understood in detail, it seems well established that intermediates arising from fatty acid oxidation are responsible for the stimulation of glucose synthesis. This is underlined by the findings from other laboratories where inhibitors of fatty acid oxidation such as a-bromopalmitate [l]

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“…The recent finding that glycodiazine. an inhibitor of lipolysis [49], does not prevent the glucagon stimulation of gluconeogenesis [50] has cast some doubts on this hypothesis. Nevertheless, the fact that the ratio lactate used : glucose formed remained unchanged after glucagon stimulation (Table 1) seems to support the idea that an enhanced lipid oxidation may be the source of the extra energy needed for glucose synthesis.…”

Section: Hepatic Cellular Metabolite Distribution and Redox Statementioning

confidence: 99%

Glucagon and Insulin Control of Gluconeogenesis in the Perfused Isolated Rat Liver. Effects on Cellular Metabolite Distribution

1975

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The metabolic effects of glucagon and glucagon plus insulin on the isolated rat livers perfused with 10 mM sodium L-lactate as substrate were studied. Glucagon stimulated gluconeogenesis, ketogenesis and ureogenesis at the concentration used of 2.1 nM. The addition of insulin to give a glucagon-to-insulin ratio of 0.2 reversed all the glucagon effects.The glucagon enhancement of gluconeogenesis was accompanied by a rise in the cytosolic and mitochondrial state of reduction of the NAD system and a fall in the [ATP]/[ADP] ratio. The analysis of the intermediary metabolite concentrations suggested, as possible sites of glucagon action, the steps between pyruvate and phosphoenolpyruvate as well as the reactions catalyzed by phosphofructokinase and/or fructose bisphosphatase. All the changes in metabolite contents were abolished when insulin was present.Glucagon increased the intramitochondrial concentration of all the metabolites, whose intracellular distribution was calculated. The finding of a significant rise in the calculated intramitochondrial concentration of oxaloacetate points to pyruvate carboxylation as an important site of glucagon interaction with the gluconeogenic pathway. A primary event in the glucagon action redistributing intracellular metabolites seems to be the mitochondrial entry of malate. The possibility is discussed that the changes in metabolite cellular distribution were brought about by the increased cellular state of reduction caused by the hormone.Since an early study, in which the role of glucagon on hepatic gluconeogenesis was postulated [l -41, a considerable amount of information has been accumulated regarding its mechanism of action. However, the efforts do not seem to have been succesful, since as yet no satisfactory explanation has been found to elucidate the mechanism leading to the enhancement of the hepatic gluconeogenic flux under the different situations in which the hormone is known to be active.Recent work has pointed to the activation of some metabolic event between pyruvate and phosphoenolpyruvate as the cause for the observed effect of glucagon stimulation of the gluconeogenic flux from subEnzymes. Aconitate hydratase (EC 4.2

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The Role of Endogenous Lipid in Gluconeogenesis and Ketogenesis of Perfused Rat Liver

Cited by 75 publications

References 39 publications

Effects of Thyroid Hormone Deficiency on the Distribution of Hepatic Metabolites and Control of Pathways of Carbohydrate Metabolism in Liver and Adipose Tissue of the Rat

Effects of Thyroid Hormone Deficiency on the Distribution of Hepatic Metabolites and Control of Pathways of Carbohydrate Metabolism in Liver and Adipose Tissue of the Rat

Interrelationship between Fatty Acid Oxidation and Gluconeogenesis from Pyruvate

Glucagon and Insulin Control of Gluconeogenesis in the Perfused Isolated Rat Liver. Effects on Cellular Metabolite Distribution

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