Quantitative analysis of glycogen repletion by nuclear magnetic resonance spectroscopy in the conscious rat.

Shulman, Gerald I.; Rossetti, Luciano; Rothman, Douglas L.; Blair, James B.; Smith, Daniel J.

doi:10.1172/jci113084

Cited by 87 publications

(87 citation statements)

References 28 publications

(26 reference statements)

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“…Male BALB/c mice (22-25 g) were injected intraperitoneally with NAC or other compounds. [U- 13 C]glucose (500 mg/kg; 2.78 mmol/kg) was injected intravenously in bolus to study metabolic changes in awake mice. Using 500 mg/kg [U- 13 C]glucose, plasma glucose was Ͻ10 mmol/L in all experiments.…”

Section: Methodsmentioning

confidence: 99%

“…[U- 13 C]glucose (500 mg/kg; 2.78 mmol/kg) was injected intravenously in bolus to study metabolic changes in awake mice. Using 500 mg/kg [U- 13 C]glucose, plasma glucose was Ͻ10 mmol/L in all experiments. To investigate the immediate metabolic effects, the animals were killed 45 minutes after injection of the study substances and [U-13 C]glucose; additional experiments were done to investigate time-dependent effects of NAC (45 minutes to 4 hours).…”

Section: Methodsmentioning

confidence: 99%

“…[13][14][15] We focused our experiments on 2 enzymatic pathways related to the TCA cycle: (1) pyruvate carboxylase (PC), which delivers new carbons into the TCA cycle, therefore allowing the synthesis of amino acids (including GSH); and (2) pyruvate dehydrogenase (PDH), a key enzyme for hepatocellular mitochondrial energy metabolism by acetyl-CoA supply. [13][14][15][16][17] We investigated liver extracts by high-resolution multinuclear ( 1 H, 31 P, 13 C) nuclear magnetic resonance (NMR) spectroscopy as an ideal method to identify and quantify metabolites without preselecting individual metabolites or prior separation. [18][19][20] Furthermore, the use of 13 C-labeled glucose allows the identification of several metabolic pathways simultaneously, such as PDH and PC.…”

mentioning

confidence: 99%

“…[13][14][15][16][17] We investigated liver extracts by high-resolution multinuclear ( 1 H, 31 P, 13 C) nuclear magnetic resonance (NMR) spectroscopy as an ideal method to identify and quantify metabolites without preselecting individual metabolites or prior separation. [18][19][20] Furthermore, the use of 13 C-labeled glucose allows the identification of several metabolic pathways simultaneously, such as PDH and PC. [13][14][15][16][17] To identify liver metabolic alterations caused by NAC, and whether these are associated with GSH synthesis, normal mice were treated with NAC or other GSH precursors.…”

mentioning

confidence: 99%

“…[18][19][20] Furthermore, the use of 13 C-labeled glucose allows the identification of several metabolic pathways simultaneously, such as PDH and PC. [13][14][15][16][17] To identify liver metabolic alterations caused by NAC, and whether these are associated with GSH synthesis, normal mice were treated with NAC or other GSH precursors. We also investigated the association of these metabolic changes with the hepatoprotection afforded by NAC in experimental liver injuries caused by (a) tertbutylhydroperoxide (t-BHP)-induced oxidative stress, and (b) 3-nitropropionic acid (3-NPA)-induced mitochondrial impairment.…”

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confidence: 99%

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Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver

Zwingmann

Bilodeau

2006

Hepatology

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The hepatoprotective mechanisms of N-acetylcysteine (NAC) in non-acetaminophen-induced liver injury have not been studied in detail. We investigated the possibility that NAC could affect key pathways of hepatocellular metabolism with or without changes in glutathione (GSH) synthesis. Hepatocellular metabolites and high-energy phosphates were quantified from mouse liver extracts by 1 H-and 31 P-NMR (nuclear magnetic resonance) spectroscopy. 13 C-NMR-isotopomer analysis was used to measure [U-13 C]glucose metabolism through pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC). NAC (150-1,200 mg/kg) increased liver concentrations of GSH from 8.60 ؎ 0.48 to a maximum of 12.95 ؎ 1.03 mol/g ww, whereas hypotaurine (HTau) concentrations increased from 0.05 ؎ 0.02 to 9.95 ؎ 1.12 mol/g ww. The limited capacity of NAC to increase GSH synthesis was attributed to impaired glucose metabolism through PC. However, 300 mg/kg NAC significantly increased the fractional 13 C-enrichment in Glu (from 2.08% ؎ 0.26% to 4.00% ؎ 0.44%) synthesized through PDH, a key enzyme for mitochondrial energy metabolism. This effect could be uncoupled from GSH synthesis and was associated with the prevention of liver injury induced by tert-butylhydroperoxide and 3-nitropropionic acid. N -acetylcysteine (NAC) is the most widely administered antidote in acetaminophen intoxication. [1][2][3][4] In this setting, protection by NAC is believed to be attributable to its ability to regenerate glutathione (GSH) stores due to its capacity to provide cysteine (Cys) residues. However, NAC has also been shown to improve patient outcome after late administration, 5,6 pointing toward mechanisms independent from GSH replenishment. Furthermore, because NAC is recognized as an antioxidant, it might be useful in the setting of liver injuries different from those caused by acetaminophen intoxication. [6][7][8][9][10][11] NAC has also been reported to improve oxygen delivery, 4 to increase systemic oxygen consumption, 12 and to have beneficial effects on liver blood flow and function. 6,8,10 Because liver oxygen consumption is coupled with aerobic oxidation of energy substrates in the mitochondrial tricarboxylic acid (TCA) cycle, we hypothesize that NAC might improve hepatocellular energy metabolism. This effect might be salutary in the setting of nonacetaminophen-induced liver injury.We were particularly interested in investigating how NAC is involved in hepatocellular metabolic pathways and whether these changes are associated with modulation of GSH synthesis. The liver is unique in its metabolic activity and harbors many interrelated pathways. Apart

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver

Zwingmann

Bilodeau

2006

Hepatology

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Simultaneous in vivo monitoring of hepatic glucose and glucose-6-phosphate by13C-NMR spectroscopy

2000

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Quantitative in vivo nuclear magnetic resonance studies of hybridoma metabolism

Sharfstein

Tucker

Mancuso

et al. 1994

Biotech & Bioengineering

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Carbon-13 nuclear magnetic resonance (NMR) spectroscopy was used to study the metabolism of a murine hybridoma cell line at two feed glutamine concentrations, 4.0 and 1.7 mM. Carbon-13 labeling patterns were used in conjunction with nutrient uptake rates to calculate the metabolic fluxes through the glycolytic pathway, the pentose shunt, the malate shunt, lipid biosynthesis, and the tricarboxylic acid (TCA) cycle. Decreasing the feed glutamine concentration significantly decreased glutamine uptake but had little effect on glucose metabolism. A significant incrase in antibody productivity occurred upon decreasing the feed glutamine level. The increased antibody productivity in concert with decreased glutamine uptake and no apparent change in glucolytic metabolism suggests that antibody production was not energy limited. Metabolic flux calculations indicate that (1) approximately 92% of the glucose consumed proceeds directly through glycolysis with 8% channeled through the pentose shunt; (2) lipid biosynthesis appears to be greater than malate shunt activity; and (3) considerable exchange occurs between TCA cycle intermediates and amino acid metabolic pools, leading to substantial loss of (13)C label from the TCA cycle. These results illustrate that (13)NMR spectroscopy is a powerfulf tool in the calculation of metabolic fluxes, particularly for exchange pathways where no net flux occurs. (c) 1994 John Wiley & Sons, Inc.

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Quantitative analysis of glycogen repletion by nuclear magnetic resonance spectroscopy in the conscious rat.

Cited by 87 publications

References 28 publications

Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver

Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver

Simultaneous in vivo monitoring of hepatic glucose and glucose-6-phosphate by13C-NMR spectroscopy

Quantitative in vivo nuclear magnetic resonance studies of hybridoma metabolism

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