Fluctuation of Hepatic Enzymes Important in Glucose Metabolism in Relation to Thyroid Function

Böttger, I.; Kriegel, H.; Wieland, O.

doi:10.1111/j.1432-1033.1970.tb00925.x

Cited by 66 publications

(27 citation statements)

References 27 publications

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“…An enhanced rate of glucose production from alanine was observed qualitatively in these studies in hepatocytes from T3-treated rats, in accord with the quantitative results of Singh and Snyder (3), who reported an increased glucose production of 160% in perfused liver from fasted hyperthyroid rats. This increase in the rate ofgluconeogenesis agrees with measurements of increased activities of hepatic pyruvate carboxylase, P-ePrv carboxykinase, and glucose-6-phosphatase (4,5) in the hyperthyroid rat and means that the increased flux ratios given in Table 4 indicate a fortiori absolute increases in flux through pyruvate kinase. Because the malic enzyme interconverts malate and pyruvate, the possibility that enhancement ofthe activity of this enzyme in the hyperthyroid state (6) contributed to the flux of label into C2 of pyruvate was examined by use of the malic enzyme inhibitor, 2,4-dihydroxybutyrate (7).…”

Section: Resultssupporting

confidence: 86%

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13C NMR study of gluconeogenesis from labeled alanine in hepatocytes from euthyroid and hyperthyroid rats.

Cohen¹,

Glynn²,

Shulman³

1981

Proc. Natl. Acad. Sci. U.S.A.

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Metabolism of [3-'3C]alanine in the presence and absence of 3-hydroxybutyrate or ethanol has been followed at 250C by 13C NMR at 90.5 MHz in primary hepatocytes from untreated rats and rats treated with triiodothyronine and not allowed to eat for 24 hr. The phosphoenolpyruvate/pyruvate futile cycle was followed in situ by comparing the concentration of 13C at the scrambled alanine C2 position with that at glucose C5. In the absence of ethanol, the flux through pyruvate kinase was 60% of the gluconeogenic flux in hepatocytes from hyperthyroid rats, compared with 25% in the controls. Incubation with ethanol reduced the pyruvate kinase flux in the hyperthyroid state to that measured in the controls. Under all conditions, the relative concentration of label at the aspartate C2 and C3 sites was 1:2, whereas at the corresponding carbons in glutamate, randomization was almost complete. These observations, which require flux of unscrambled label into aspartate, are consistent with intramitochondrial synthesis of aspartate only if there is incomplete mixing of the intramitochondrial oxaloacetate pool. The 13C enrichment measured in the ketone bodies is increased by the presence of exogenous f3-hydroxybutyrate. The greater labeling that we observe at C2 of f3-hydroxybutyrate compared with C4 under this condition is explained by the flow through 3-hydroxy-3-methylglutaryl-coenzyme A synthase.In a recent '3C NMR study of suspensions of isolated hepatocytes from euthyroid and hyperthyroid rats, we measured the flux through the gluconeogenic pathway from labeled glycerol into glucose, determined the pentose cycle activity, and examined the pathway through the nonoxidative pentose branch (1). In another study, in which we followed the metabolism of 13C-labeled alanine in perfused mouse liver, the competition between ethanol and alanine into the tricarboxylic acid cycle was investigated, and it was also suggested that the 13C NMR spectra provided a unique probe ofthe in situ flux through pyruvate kinase (2).The present 13C study shows the effect of thyroid hormone treatment upon the flux through pyruvate kinase during gluconeogenesis from labeled alanine in primary rat hepatocytes. The results confirm our previous studies in perfused mouse liver of the competition between ethanol and alanine into the tricarboxylic acid cycle. METHODS AND MATERUILSLiver parenchymal cells were isolated from male Sprague-Dawley rats (190-240 g) that had not eaten for 24 hr. The animals received intraperitoneal injections of either L-3,3',5-triiodothyronine (T3; Calbiochem, B grade) dissolved in isotonic saline at pH 9.8, 8 jig of T3 per 100 g of body weight per day (T3-treated, hyperthyroid), or isotonic saline alone (or no injections) (euthyroid control) for 4 days prior to cell preparation.The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.The liver cell preparation, the resuspens...

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Section: Resultssupporting

confidence: 86%

“…The animals received intraperitoneal injections of either L-3,3',5-triiodothyronine (T3; Calbiochem, B grade) dissolved in isotonic saline at pH 9.8, 8 jig of T3 per 100 g of body weight per day (T3-treated, hyperthyroid), or isotonic saline alone (or no injections) (euthyroid control) for 4 days prior to cell preparation.…”

Section: Methods and Materuilsmentioning

confidence: 99%

13C NMR study of gluconeogenesis from labeled alanine in hepatocytes from euthyroid and hyperthyroid rats.

Cohen¹,

Glynn²,

Shulman³

1981

Proc. Natl. Acad. Sci. U.S.A.

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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: 67%

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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“…In addition, these reduced enzyme activities were restored to normal levels by a single injection of T3 (12,13). Viewed together these data suggest the possibility that the synthesis of protein kinase decreases in the liver in hypothyroid animals.…”

Section: Discussionmentioning

confidence: 53%

Effects of phenylephrine and isoproterenol on the activity of cyclic AMP-dependent protein kinase of hypothyroid rat tissues.

1979

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Abstract-The present study was designed to examine the properties of cyclic AMP dependent protein kinase from normal and hypothyroid rat tissues. The activity of the liver enzyme decreased in hypothyroid rats and this reduced activity may be due to the decrease in synthesis of enzyme protein. The enzyme activity from the kidney of hypothyroid rats increased by 35% in the absence of cyclic AMP. Further, the enzyme from the kidney of hypothyroid animals responded to phenylephrine and isoproterenol.In the heart, the basal enzyme activity was the same in both groups, but the enzyme from the heart of hypothyroid animals did not respond to isoproterenol. When hypothyroid rats were treated with 3,3',5-triiodothyronine, the enzyme activities from those rat tissues showed essentially the same level as those of the corresponding normal ones. These results suggest that thyroid hormone regulates adrenergic agonists mediated responses both at the sites of adrenoceptors and that of protein phosphory lation. Furthermore, the dependence on thyroid hormone varies according to the tissue.Thyroid hormone plays an important role in the regulation of adrenergic agonists mediated responses in tissues from several species (1). There may be at least two sites of action of thyroid hormone in regard to this mechanism: one is the adrenoceptors including adenylate cyclase and the other the intracellular processes after the formation of the agonists receptor complex.In our laboratory, we found that the increased response of a-adrenoceptors of hearts from hypothyroid rats to phenylephrine and decreased response of jj-adrenoceptors of hearts and livers from hypothyroid rats to isoproterenol could not be explained by changes in intracellular contents of cyclic AMP. It has also been suggested that the decreased sensitivity of i3-adrenoceptor in the liver and heart might account for the change in enzyme activities involved in cyclic AMP metabolism (2-5).The present study was carried out to compare the cyclic AMP-dependent protein kinase activity of normal and hypothyroid rats and to examine the effects of adrenergic agonists on this enzyme. The possible physiological relationship between thyroid hormone and adrenergic agonists is discussed. MATERIALS AND METHODSMale Wistar strain rats were used throughout the experiments. Rats were made hypo

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Fluctuation of Hepatic Enzymes Important in Glucose Metabolism in Relation to Thyroid Function

Cited by 66 publications

References 27 publications

13C NMR study of gluconeogenesis from labeled alanine in hepatocytes from euthyroid and hyperthyroid rats.

13C NMR study of gluconeogenesis from labeled alanine in hepatocytes from euthyroid and hyperthyroid rats.

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 phenylephrine and isoproterenol on the activity of cyclic AMP-dependent protein kinase of hypothyroid rat tissues.

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