Activation of the KATP channel-independent signaling pathway by the nonhydrolyzable analog of leucine, BCH

2003 ◽  
Vol 285 (2) ◽  
pp. E380-E389 ◽  
Author(s):  
Yi-Jia Liu ◽  
Haiying Cheng ◽  
Heather Drought ◽  
Michael J. MacDonald ◽  
Geoffrey W. G. Sharp ◽  
...  
Keyword(s):  
Tca Cycle ◽  
Acid Oxidation ◽  
Biphasic Response ◽  
Glucose Signaling ◽  
Palmitate Oxidation ◽  
Biphasic Insulin ◽  
The Tca Cycle ◽  
Full Effect ◽  
Biphasic Insulin Release ◽  
Stimulation Of

Leucine and glutamine were used to elicit biphasic insulin release in rat pancreatic islets. Leucine did not mimic the full biphasic response of glucose. Glutamine was without effect. However, the combination of the two did mimic the biphasic response. When the ATP-sensitive K+ (KATP) channel-independent pathway was studied in the presence of diazoxide and KCl, leucine and its nonmetabolizable analog 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) both stimulated insulin secretion to a greater extent than glucose. Glutamine and dimethyl glutamate had no effect. Because the only known action of BCH is stimulation of glutamate dehydrogenase, this is sufficient to develop the full effect of the KATP channel-independent pathway. Glucose, leucine, and BCH had no effect on intracellular citrate levels. Leucine and BCH both decreased glutamate levels, whereas glucose was without effect. Glucose and leucine decreased palmitate oxidation and increased esterification. Strikingly, BCH had no effect on palmitate oxidation or esterification. Thus BCH activates the KATP channel-independent pathway of glucose signaling without raising citrate levels, without decreasing fatty acid oxidation, and without mimicking the effects of glucose and leucine on esterification. The results indicate that increased flux through the TCA cycle is sufficient to activate the KATP channel-independent pathway.

Ethyl pyruvate stabilizes hypoxia-inducible factor 1 alpha via stimulation of the TCA cycle

2010 ◽  
Vol 295 (2) ◽  
pp. 236-241 ◽  
Author(s):  
Seon-Ye Kim ◽  
Jae-Sun Choi ◽  
Chan Park ◽  
Joo-Won Jeong
Keyword(s):  
Ethyl Pyruvate ◽  
Hypoxia Inducible Factor ◽  
Tca Cycle ◽  
Hypoxia Inducible Factor 1 ◽  
The Tca Cycle ◽  
Stimulation Of

Development of the biphasic response to glucose in fetal and neonatal rat pancreas

1988 ◽  
Vol 254 (2) ◽  
pp. E167-E174 ◽  
Author(s):  
R. L. Hole ◽  
M. C. Pian-Smith ◽  
G. W. Sharp
Keyword(s):  
Beta Cell ◽  
Insulin Release ◽  
Neonatal Rat ◽  
Biphasic Response ◽  
Rat Pancreas ◽  
K Channels ◽  
Fetal Pancreas ◽  
Biphasic Insulin ◽  
Biphasic Insulin Release ◽  
Ca2 Channels

A study on the development of biphasic insulin release and sensitivity to inhibitors has been performed using perifused rat pancreas at 19.5 days of gestation (3 days before birth) and at 3 days after birth. In the fetal pancreas, 16.7 mM glucose caused a marked stimulation of insulin release that did not, however, manifest a biphasic response and was not inhibited by verapamil, a Ca2+ channel blocker. This suggested that the immature response was due to either a lack of voltage-dependent Ca2+ channels or their failure to open in response to glucose. Depolarizing concentrations of KCl stimulated insulin release, which was inhibited by verapamil, demonstrating that functional Ca2+ channels were present. In the presence of 16.7 mM glucose, quinine, which blocks glucose-sensitive k+ channels, potentiated the response of the fetal pancreas that now became sensitive to verapamil, demonstrating that functional K+ channels were also present in the fetal pancreatic beta-cell. The immaturity of the response is not due specifically to a defect in glucose metabolism; rather the metabolism of nutrient secretagogues fails to couple with the K+ channel in the fetal islet and thus fails to depolarize the beta-cell membrane. Three days after birth the pattern of response to high glucose is biphasic. Insulin release in fetal pancreas was inhibited by epinephrine and somatostatin.

scholarly journals Metabolic Derangement in Polycystic Kidney Disease Mouse Models Is Ameliorated by Mitochondrial-Targeted Antioxidants

2021 ◽  
Author(s):  
Nastaran Daneshgar ◽  
Andrew W Baguley ◽  
Peir-In Liang ◽  
Fei Wu ◽  
Yi Chu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Tca Cycle ◽  
Acid Oxidation ◽  
Polycystic Kidney ◽  
Metabolic Derangement ◽  
Beneficial Effects ◽  
Mitochondrial Ros ◽  
The Tca Cycle

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.

scholarly journals Recovery of labeled CO2 from acetate in severely burned children

2007 ◽  
Vol 293 (6) ◽  
pp. E1726-E1729 ◽  
Author(s):  
Ricki Y. Fram ◽  
Melanie G. Cree ◽  
David L. Chinkes ◽  
David N. Herndon ◽  
Robert R. Wolfe
Keyword(s):  
Fatty Acids ◽  
Indirect Calorimetry ◽  
Recovery Rate ◽  
Isotope Ratio Mass Spectrometry ◽  
Tca Cycle ◽  
Acid Oxidation ◽  
Exchange Reactions ◽  
Isotopic Enrichment ◽  
High Recovery Rate ◽  
The Tca Cycle

The purpose of this study was to determine the fractional recovery rate of labeled CO2 in the breath of severely burned children. This information is needed to perform tracer studies of substrate oxidation using carbon-labeled fatty acids. Nine children, ages 4–14 yr with massive burns participated in the study. All experiments were performed 7 days post burn after an overnight fast. A primed (60 μmol/kg), constant (2.0 μmol·kg−1·min−1) infusion of [1,2-13C]acetate was given during a 4-h basal period and during a 4-h hyperinsulinemic euglycemic clamp. A priming dose (150 μmol/kg) of NaH13CO3 was given at the beginning of the study. Breath samples were collected every 10 min during the last 40 min of each period. Indirect calorimetry was performed during the last 30 min of each period. The isotopic enrichment of 13CO2 was determined by isotope ratio-mass spectrometry, and total CO2 excretion was measured by indirect calorimetry. The fractional recovery of acetate label was 0.89 ± 0.05 and 0.88 ± 0.04 during the basal state and clamp, respectively. We conclude that the fractional recovery of labeled acetate in severely burned children is approximately three times the recovery of a nonburned adult and similar to the value in exercising adults. The high recovery rate reflects the rapid turnover of the TCA cycle in burned children relative to the rate of exchange reactions. Minimal correction of expired CO2 data is needed in this circumstance to quantify fatty acid oxidation using 13C-labeled fatty acids.

scholarly journals What Constitutes a Gluconeogenic Precursor?

2020 ◽  
Vol 150 (9) ◽  
pp. 2239-2241
Author(s):  
Mark A Tetrick ◽  
Jack Odle
Keyword(s):  
Carbon Dioxide ◽  
Fatty Acids ◽  
Chain Length ◽  
Tricarboxylic Acid Cycle ◽  
Glyoxylate Cycle ◽  
Tca Cycle ◽  
Acid Oxidation ◽  
The Tca Cycle ◽  
Glucose Synthesis ◽  
Tca Cycle Intermediates

ABSTRACT A gluconeogenic precursor is a biochemical compound acted on by a gluconeogenic pathway enabling the net synthesis of glucose. Recognized gluconeogenic precursors in fasting placental mammals include glycerol, lactate/pyruvate, certain amino acids, and odd-chain length fatty acids. Each of these precursors is capable of contributing net amounts of carbon to glucose synthesis via the tricarboxylic acid cycle (TCA cycle) because they are anaplerotic, that is, they are able to increase the pools of TCA cycle intermediates by the contribution of more carbon than is lost via carbon dioxide. The net synthesis of glucose from even-chain length fatty acids (ECFAs) in fasting placental mammals, via the TCA cycle alone, is not possible because equal amounts of carbon are lost via carbon dioxide as is contributed from fatty acid oxidation via acetyl-CoA. Therefore, ECFAs do not meet the criteria to be recognized as a gluconeogenic precursor via the TCA cycle alone. ECFAs are gluconeogenic precursors in organisms with a functioning glyoxylate cycle, which enables the net contribution of carbon to the intermediates of the TCA cycle from ECFAs and the net synthesis of glucose. The net conversion of ECFAs to glucose in fasting placental mammals via C3 metabolism of acetone may be a competent though inefficient metabolic path by which ECFA could be considered a gluconeogenic precursor. Defining a substrate as a gluconeogenic precursor requires careful articulation of the definition, organism, and physiologic conditions under consideration.

scholarly journals Metabolic derangement in polycystic kidney disease mouse models is ameliorated by mitochondrial-targeted antioxidants

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Nastaran Daneshgar ◽  
Andrew W. Baguley ◽  
Peir-In Liang ◽  
Fei Wu ◽  
Yi Chu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Mouse Models ◽  
Tca Cycle ◽  
Acid Oxidation ◽  
Polycystic Kidney ◽  
Metabolic Derangement ◽  
Beneficial Effects ◽  
Mitochondrial Ros ◽  
The Tca Cycle

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1RC/null and PKD1RC/RC. Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD.

scholarly journals Lipin-1 regulates lipid catabolism in pro-resolving macrophages

2020 ◽  
Author(s):  
Robert M. Schilke ◽  
Cassidy M.R. Blackburn ◽  
Shashanka Rao ◽  
David Krzywanski ◽  
Brian N. Finck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Apoptotic Cell ◽  
Lipid Synthesis ◽  
Tca Cycle ◽  
Acid Oxidation ◽  
Lipid Catabolism ◽  
Phosphatidic Acid Phosphatase ◽  
The Tca Cycle ◽  
Lipin 1

AbstractMacrophages reprogram their metabolism to promote appropriate responses. Pro-resolving macrophages primarily utilize fatty acid oxidation as an energy source. Metabolites generated during the catabolism of fatty acids aid in the resolution of inflammation and tissue repair, but the regulatory mechanisms that control lipid metabolism in macrophages is not fully elucidated. In this current study we show that lipin-1, a phosphatidic acid phosphatase and regulator of lipid metabolism, is required for increased oxidative phosphorylation during IL-4 mediated responses. We also show that the transcriptional coregulatory function of lipin-1 is required for β-oxidation in response to palmitate (free fatty acid) and apoptotic cell derived lipids. BMDMs lacking lipin-1 have a reduction in critical TCA cycle metabolites following IL-4 stimulation, suggesting a break in the TCA cycle that is supportive of lipid synthesis rather than lipid catabolism. Together, our data demonstrate that lipin-1 regulates intermediary metabolism within pro-resolving macrophages and highlights the importance of aligning macrophage metabolism with proper responses to stimuli.

Liquid-liquid extraction of succinate using a dicopper cryptate

2020 ◽  
Author(s):  
Riccardo Mobili ◽  
Sonia La Cognata ◽  
Francesca Merlo ◽  
Andrea Speltini ◽  
Massimo Boiocchi ◽  
...  
Keyword(s):  
Aqueous Phase ◽  
Visible Spectrum ◽  
Tca Cycle ◽  
Residual Concentration ◽  
Waste Products ◽  
Liquid Liquid Extraction ◽  
The Tca Cycle ◽  
Quantitative Extraction ◽  
Uv Visible

<div> <p>The extraction of the succinate dianion from a neutral aqueous solution into dichloromethane is obtained using a lipophilic cage-like dicopper(II) complex as the extractant. The quantitative extraction exploits the high affinity of the succinate anion for the cavity of the azacryptate. The anion is effectively transferred from the aqueous phase, buffered at pH 7 with HEPES, into dichloromethane. A 1:1 extractant:anion adduct is obtained. Extraction can be easily monitored by following changes in the UV-visible spectrum of the dicopper complex in dichloromethane, and by measuring the residual concentration of succinate in the aqueous phase by HPLC−UV. Considering i) the relevance of polycarboxylates in biochemistry, as e.g. normal intermediates of the TCA cycle, ii) the relevance of dicarboxylates in the environmental field, as e.g. waste products of industrial processes, and iii) the recently discovered role of succinate and other dicarboxylates in pathophysiological processes including cancer, our results open new perspectives for research in all contexts where selective recognition, trapping and extraction of polycarboxylates is required. </p> </div>

scholarly journals Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

2021 ◽  
Vol 22 (5) ◽  
pp. 2746
Author(s):  
Dimitri Shcherbakov ◽  
Reda Juskeviciene ◽  
Adrián Cortés Sanchón ◽  
Margarita Brilkova ◽  
Hubert Rehrauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Response ◽  
Mitochondrial Gene ◽  
Tca Cycle ◽  
Brain Mitochondria ◽  
Mitochondrial Gene Expression ◽  
Rna Seq ◽  
The Tca Cycle ◽  
Neurological Phenotype

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

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