Some effects of glucocorticoids on the subcellular distribution of the activities of citrate synthase and phosphoenolpyruvate carboxykinase in livers of rats and cows

Heitzman, R.J.; Herriman, I. D.; Mallinson, C.B.

doi:10.1016/0014-5793(72)80006-1

Cited by 21 publications

(8 citation statements)

References 9 publications

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“…Unlike most eutherian mammals where PEPCK-M is significant compared with PEPCK-C, the prevailing opinion is that the rat has little or no detectable hepatic PEPCK-M activity. Compartmentalization of PEPCK to the cytosol and mitochondria of the rat has been compared mostly by measuring enzymatic activity either directly or indirectly in fractions of tissue homogenate with the percentage of PEPCK-M activity ranging from undetectable (6, 28), 5% (29), 6% (30), 10% (31),18% (32), 25% (33, 34), to 50% (35). This approach has inherent weaknesses inasmuch as the assumption is made that enzymatic activities under the assayed condition, are representative of metabolic flux within each of these compartments in a living cell.…”

Section: Discussionmentioning

confidence: 99%

Phosphoenolpyruvate Cycling via Mitochondrial Phosphoenolpyruvate Carboxykinase Links Anaplerosis and Mitochondrial GTP with Insulin Secretion

Stark

Pasquel

Turcu

et al. 2009

Journal of Biological Chemistry

134

159

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Pancreatic β-cells couple the oxidation of glucose to the secretion of insulin. Apart from the canonical KATP-dependent glucose-stimulated insulin secretion (GSIS), there are important KATP-independent mechanisms involving both anaplerosis and mitochondrial GTP (mtGTP). How mtGTP that is trapped within the mitochondrial matrix regulates the cytosolic calcium increases that drive GSIS remains a mystery. Here we have investigated whether the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) is the GTPase linking hydrolysis of mtGTP made by succinyl-CoA synthetase (SCS-GTP) to an anaplerotic pathway producing phosphoenolpyruvate (PEP). Although cytosolic PEPCK (PEPCK-C) is absent, PEPCK-M message and protein were detected in INS-1 832/13 cells, rat islets, and mouse islets. PEPCK enzymatic activity is half that of primary hepatocytes and is localized exclusively to the mitochondria. Novel 13C-labeling strategies in INS-1 832/13 cells and islets measured substantial contribution of PEPCK-M to the synthesis of PEP. As high as 30% of PEP in INS-1 832/13 cells and 41% of PEP in rat islets came from PEPCK-M. The contribution of PEPCK-M to overall PEP synthesis more than tripled with glucose stimulation. Silencing the PEPCK-M gene completely inhibited GSIS underscoring its central role in mitochondrial metabolism-mediated insulin secretion. Given that mtGTP synthesized by SCS-GTP is an indicator of TCA flux that is crucial for GSIS, PEPCK-M is a strong candidate to link mtGTP synthesis with insulin release through anaplerotic PEP cycling.

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Section: Discussionmentioning

confidence: 99%

Phosphoenolpyruvate Cycling via Mitochondrial Phosphoenolpyruvate Carboxykinase Links Anaplerosis and Mitochondrial GTP with Insulin Secretion

Stark

Pasquel

Turcu

et al. 2009

Journal of Biological Chemistry

134

159

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“…Baird & Heitzman (1971) showed that the treatment of ketotic cows with the glucocorticoid dexamethasone 21-isonicotinate, decreased ketone body concentration and increased citrate values. The mechanism involved in promoting this antiketogenic effect was investigated by Heitzman, Herriman & Mallinson (1972), who showed that in treated animals there was diminished activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase in the cytoplasmic fraction of the liver cell, and an increase in citrate synthase activity in the mitochondrial and cytoplasmic fraction. The increase in citrate synthase would favour a flow of oxaloacetate to citrate, while the decrease of cytoplasmic phosphoenolpyruvate carboxykinase would tend to diminish gluconeogenesis.…”

Section: Discussionmentioning

confidence: 99%

The effects of fasting on the concentrations of intermediate metabolites in the blood and hepatic tissues of pregnant and non-pregnant ewes

Herriman

Heitzman

1978

J. Agric. Sci.

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Blood and liver samples were taken from four fasted pregnant and five fasted nonpregnant Finnish Landrace x Dorset Horn ewes. The following metabolites were measured: adenine monophosphate (AMP), adenine diphosphate (ADP), adenine triphosphate (ATP), citrate, 2-oxoglutarate, phosphoenolpyruvate, pyruvate, lactate, 2-phosphoglyeerate, 3-phosphoglycerate, a-glycerophosphate, malate, /?-hydroxybutyrate, acetoacetate, glutamate, alanine and NAD + .The effects of a 6-day fast on non-pregnant ewes were shown as significant reductions in the hepatic concentrations of 2-phosphoglycerate, alanine, NAD+ and ADP, together with significant increases in the hepatic concentrations of 3-hydroxybutyrate, malate and the ratio of 3-hydroxybutyrate:acetoacetate. In the blood there were significant reductions in the concentrations of urea, citrate and in the ratio of 3-hydroxybutyrate: acetoacetate.Similar but more marked changes occurred in the late pregnant ewes, with additional significant reductions in the hepatic concentrations of citrate, ATP and the level of cell energy, and additional increases in the blood of the ratio of lactate: pyruvate and the concentrations of 3-hydroxybutyrate and 2-oxoglutarate. However, unlike the nonpregnant ewes no significant changes in either the plasma concentration of urea or the hepatic concentration of ADP were observed in the late pregnant ewes.strates were given to sheep the rate of glucose synthesis increased, so that the control of glucose The effect of undernutrition on Suffolk cross-metabolism is centred around the availability of bred ewes late in pregnancy was investigated by glucogenic precursors. However, it has been shown Patterson et al. (1964), and they attempted to in ruminants that gluconeogenesis is increased relate the changes in the levels of plasma glucose, during pregnancy (Bergman, 1963; Ford, 1963;

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“…Guinea pig liver and kidney has about 80% PEPCK-M activity. While perhaps the most cited references suggest that the rat and the mouse have a PEPCK-C/PEPCK-M ratio of 9 to 1 [76], some authors [82-85] detected more than 10% PEPCK-M activity in rodent liver. These discrepancies may be due to the differences in the enzymatic activity assay used ( Table 1 and reviewed in [7]).…”

Section: Pepck-mmentioning

confidence: 99%

“…Besides the general view that PEPCK-M is not sufficiently active in rodent liver, a few publications ( Table 1 ) [82-85, 135] suggest contrary and would challenge the above mentioned studies [137, 146, 147]. Surprisingly, in the livers of chronically glucose-infused rats, a model of Type-2 diabetes with inappropriate increases in glucagon and insulin, PEPCK-C was suppressed but PEPCK-M increased in accordance with endogenous glucose production rates [135].…”

Section: Is There a Role Of Pepck-m In Gluconeogenesis?mentioning

confidence: 99%

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: Has it been overlooked?

Stark

Kibbey

2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Plasma glucose levels are tightly regulated within a narrow physiologic range. Insulin-mediated glucose uptake by tissues must be balanced by the appearance of glucose from nutritional sources, glycogen stores, or gluconeogenesis. In this regard, a common pathway regulating both glucose clearance and appearance has not been described. The metabolism of glucose to produce ATP is generally considered to be the primary stimulus for insulin release from beta-cells. Similarly, gluconeogenesis from phosphoenolpyruvate (PEP) is believed to be the primarily pathway via the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). These models cannot adequately explain the regulation of insulin secretion or gluconeogenesis. Scope of review A metabolic sensing pathway involving mitochondrial GTP (mtGTP) and PEP synthesis by the mitochondrial isoform of PEPCK (PEPCK-M) is associated with glucose-stimulated insulin secretion from pancreatic beta-cells. Here we examine whether there is evidence for a similar mtGTP-dependent pathway involved in gluconeogenesis. In both islets and the liver, mtGTP is produced at the substrate level by the enzyme succinyl CoA synthetase (SCS-GTP) with a rate proportional to the TCA cycle. In the beta-cell PEPCK-M then hydrolyzes mtGTP in the production of PEP that, unlike mtGTP, can escape the mitochondria to generate a signal for insulin release. Similarly, PEPCK-M and mtGTP might also provide a significant source of PEP in gluconeogenic tissues for the production of glucose. This review will focus on the possibility that PEPCK-M, as a sensor for TCA cycle flux, is a key mechanism to regulate both insulin secretion and gluconeogenesis suggesting conservation of this biochemical mechanism in regulating multiple aspects of glucose homeostasis. Moreover, we propose that this mechanism may be more important for regulating insulin secretion and gluconeogenesis compared to canonical nutrient sensing pathways. Major conclusions PEPCK-M, initially believed to be absent in islets, carries a substantial metabolic flux in beta-cells. This flux is intimately involved with the coupling of glucose-stimulated insulin secretion. PEPCK-M activity may have been similarly underestimated in glucose producing tissues and could potentially be an unappreciated but important source of gluconeogenesis. General Significance The generation of PEP via PEPCK-M may occur via a metabolic sensing pathway important for regulating both insulin secretion and gluconeogenesis.

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Some effects of glucocorticoids on the subcellular distribution of the activities of citrate synthase and phosphoenolpyruvate carboxykinase in livers of rats and cows

Cited by 21 publications

References 9 publications

Phosphoenolpyruvate Cycling via Mitochondrial Phosphoenolpyruvate Carboxykinase Links Anaplerosis and Mitochondrial GTP with Insulin Secretion

Phosphoenolpyruvate Cycling via Mitochondrial Phosphoenolpyruvate Carboxykinase Links Anaplerosis and Mitochondrial GTP with Insulin Secretion

The effects of fasting on the concentrations of intermediate metabolites in the blood and hepatic tissues of pregnant and non-pregnant ewes

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) and glucose homeostasis: Has it been overlooked?

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