Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon

Groen, Albert K.; Roermund, C. W. T. van; Vervoorn, Richard C.; Tager, J. M.

doi:10.1042/bj2370379

Cited by 168 publications

(104 citation statements)

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“…4), further supporting the hypothesis that both PC and PEPCK are important regulators in gluconeogenesis. 7 Increased glucagon effect.. In diabetes, pathological alteration of the precise balance between insulin and glucagon action results in excessive hepatic gluconeogenesis and glycogenolysis, both of which induce hyperglycemia.…”

Section: Discussionmentioning

confidence: 99%

“…However, deletion of PEPCK reduced gluconeogenic flux by only 40%, 6 suggesting that PC may play a more-central role in controlling gluconeogenesis. 7 In this study, we investigated the effect of insulin resistance on in vivo gluconeogenic flux in high-fat diet (HFD)-fed mice with real-time measurements of hyperpolarized [1-13 C]pyruvate anaplerosis into the tricarboxylic acid (TCA) cycle by PC, as well as its transamination into [1-13 C]alanine catalyzed by alanine transaminase (ALT). We also evaluated the sensitivity of hyperpolarized 13 C MRS in detecting changes in hepatic glucose production upon pharmacological intervention.…”

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confidence: 99%

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In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

et al. 2013

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The pathogenesis of type 2 diabetes is characterized by impaired insulin action and increased hepatic glucose production (HGP). Despite the importance of hepatic metabolic aberrations in diabetes development, there is currently no molecular probe that allows measurement of hepatic gluconeogenic pathways in vivo and in a noninvasive manner. In this study, we used hyperpolarized carbon 13 ( 13 C)-labeled pyruvate magnetic resonance spectroscopy (MRS) to determine changes in hepatic gluconeogenesis in a high-fat diet (HFD)-induced mouse model of type 2 diabetes. Compared with mice on chow diet, HFD-fed mice displayed higher levels of oxaloacetate, aspartate, and malate, along with increased 13 C label exchange rates between hyperpolarized [1-13 C]pyruvate and its downstream metabolites, [1-13 C]malate and [1-13 C]aspartate. Biochemical assays using liver extract revealed up-regulated malate dehydrogenase activity, but not aspartate transaminase activity, in HFD-fed mice. Moreover, the 13 C label exchange rate between [1-13 C]pyruvate and [1-13 C]aspartate (k pyr->asp ) exhibited apparent correlation with gluconeogenic pyruvate carboxylase (PC) activity in hepatocytes. Finally, up-regulated HGP by glucagon stimulation was detected by an increase in aspartate signal and k pyr->asp , whereas HFD mice treated with metformin for 2 weeks displayed lower production of aspartate and malate, as well as reduced k pyr->asp and 13 C-label exchange rate between pyruvate and malate, consistent with down-regulated gluconeogenesis. Conclusion: Taken together, we demonstrate that increased PC flux is an important pathway responsible for increased HGP in diabetes development, and that pharmacologically induced metabolic changes specific to the liver can be detected in vivo with a hyperpolarized 13 C-biomolecular probe. Hyperpolarized 13 C MRS and the determination of metabolite exchange rates may allow longitudinal monitoring of liver function in disease development. (HEPATOLOGY 2013;57:515-524) T he coordinated actions of insulin and glucagon ensure that glucose homeostasis is maintained across a wide range of physiological conditions. In obesity-associated type 2 diabetes, control of glucose metabolism by these two regulatory hormones is impaired, resulting in hepatic insulin resistance and excessive endogenous glucose production. 1 To date, it has not been possible to evaluate this metabolic dysfunction in the liver by a noninvasive in vivo method.Carbon-13 ( 13 C) magnetic resonance spectroscopy (MRS) has been used to study hepatic gluconeogenesis since the 1980s. However, its inherent low sensitivity has largely limited its application to the study of steady-state metabolism in perfused livers with long Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; 13 C, carbon-13; ChREBP, carbohydrate response element-binding protein; FAS, fatty acid synthase; G-6-Pase, glucose-6-phosphatase; HFD, high-fat diet; HGP, hepatic glucose production; IHTG, intrahepatic triglyceride; IPGTT, intraperitoneal glucose toleranc...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

et al. 2013

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“…The importance of this change in paradigm cannot be overestimated, especially for molecular biologists who try to metabolically engineer plants by altering the gene expression level of a single encoded enzyme. Despite its sound theoretical basis and successful practical applications (Groen et al, 1986;Giersch, 1995;Krauss and Quant, 1996;Thomas et al, 1997;Poolman et al, 2000), MCA is still not a regular tool in plant studies. Potential reasons for this may be found in practical difficulties that researchers encounter who try to determine and to utilize MCA control coefficients, which have been summarized by ap Rees and Hill (1994).…”

Section: Modelling Based On Metabolic Flux Measurementsmentioning

confidence: 99%

Metabolomics — the link between genotypes and phenotypes

Fiehn

2002

Functional Genomics

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Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms 'transcriptome' and 'proteome', the set of metabolites synthesized by a biological system constitute its 'metabolome'. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.

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“…4D shows the relationships between the cellular concentrations of DHAP and that of fructose 6-phosphate, permitting the investigation of the fructose-1,6-bisphosphatase/phosphofructokinase step. It is assumed that both aldolase-and triosephosphate isomerase work near equilibrium (31,42); therefore, DHAP concentration probably reflects the fructose 1,6-bisphosphate free concentration. From Fig.…”

Section: Kinetics Of Changes Of Dha Metabolism By Exogenousmentioning

confidence: 99%

“…The steps located between DHAP and PEP are believed to be at a near equilibrium state with the cytosolic redox state and ATPto-ADP ratio (31,42,45). Therefore, the relationship between DHAP and PEP concentrations is dependent on the potential effect of Mg-ATP on both redox state and cytosolic ATP-to-ADP ratio.…”

Section: Effect Of Mg-atp On Liver Cell Respiration Redox State Andmentioning

confidence: 99%

Exogenous Mg-ATP Induces a Large Inhibition of Pyruvate Kinase in Intact Rat Hepatocytes

Ichaï¹,

El-Mir²,

Nogueira

et al. 2001

Journal of Biological Chemistry

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Mg-ATP infusion in vivo has been reported to be beneficial both to organ function and survival rate in various models of shock. Moreover, a large variety of metabolic effects has been shown to occur in several tissues due to purinergic receptor activation. In the present work we studied the effects of exogenous Mg-ATP in rat liver cells perifused with dihydroxyacetone to investigate simultaneously gluconeogenetic and glycolytic pathways. We found a significant effect on oxidative phosphorylation as characterized by a decrease in oxygen consumption rate and in the cellular ATP-to-ADP ratio associated with an increase in lactate-to-pyruvate ratio. In addition, exogenous Mg-ATP induced rapid and reversible inhibition of both gluconeogenesis and glycolysis. The main effect on gluconeogenesis was located at the level of the fructose cycle, whereas the decrease in glycolysis was due to a strong inhibition of pyruvate kinase. Although pyruvate kinase inhibition induced by exogenous Mg-ATP was allosteric when assessed in vitro after enzyme extraction, we found a large decrease in the apparent maximal velocity when kinetics were assessed in vivo in intact perifused hepatocytes. This newly described short-term regulation of pyruvate kinase occurs only in the intact cell and may open new potentials for the pharmacological regulation of pyruvate kinase in vivo.Numerous publications have emphasized the beneficial role of Mg-ATP infusion in various models of shock or severe trauma in animals. Dysfunction of heart (1), kidney (2), muscle (3), endothelial (4), and immune cells (5, 6) are all improved by this treatment, which significantly increases the survival rate. Because such a benefit was independent of hemodynamic status (4, 7), a metabolic mechanism was proposed (8). Because the liver plays a central role in the metabolic response to such severe illnesses, it may represent a major target for Mg-ATP (9, 10).It is well known that purinergic receptor activation is responsible for a large variety of metabolic effects (11-24). ATP or adenosine or several analogues of purinergic receptors have been noted to affect liver glucose metabolism: i.e. stimulation of glycogenolysis (12, 13), increase (19,25,26) or decrease (11) of gluconeogenesis, and decrease of glycolysis (25). These effects have been related to a cAMP-dependent mechanism (12), a cAMP-independent inositol 3-phosphate/calcium-mediated signaling (13,14,16,18,21,23), a phospholipase C activation (18), or a transcriptional effect (25). It must be noted, however, that if some effects are shared among the adenine nucleotide family, others appear to be specific (12,14,18), suggesting that different signaling pathways may be involved.Because the beneficial effects were observed in vivo with Mg-ATP but not with adenosine (8, 27), we investigated the metabolic effects of exogenous Mg-ATP in rat liver cells perifused with DHA.1 Besides a significant effect on oxidative phosphorylation and on gluconeogenesis, we found that Mg-ATP was responsible for a large inhibition of pyruva...

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Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon

Cited by 168 publications

References 44 publications

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

Metabolomics — the link between genotypes and phenotypes

Exogenous Mg-ATP Induces a Large Inhibition of Pyruvate Kinase in Intact Rat Hepatocytes

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