Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 6 of 6

Publication Record

Connections

Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
0 Communities
1 Members
0 Resources
15 MeSH Terms
EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection.
Olenchock BA, Moslehi J, Baik AH, Davidson SM, Williams J, Gibson WJ, Chakraborty AA, Pierce KA, Miller CM, Hanse EA, Kelekar A, Sullivan LB, Wagers AJ, Clish CB, Vander Heiden MG, Kaelin WG
(2016) Cell 164: 884-95
MeSH Terms: Animals, Hypoxia-Inducible Factor-Proline Dioxygenases, Ischemia, Ischemic Preconditioning, Ketoglutaric Acids, Kynurenic Acid, Liver, Mice, Models, Animal, Myocardial Reperfusion Injury, Parabiosis
Show Abstract · Added March 6, 2016
Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Introduction: Metals in Biology: α-Ketoglutarate/Iron-Dependent Dioxygenases.
Guengerich FP
(2015) J Biol Chem 290: 20700-1
MeSH Terms: 5-Methylcytosine, AlkB Homolog 4, Lysine Demethylase, DNA, DNA Damage, DNA Repair, Dioxygenases, Epigenesis, Genetic, Gene Expression, Humans, Iron, Isoenzymes, Ketoglutaric Acids, Multigene Family, Oxidation-Reduction, Protein Processing, Post-Translational, Thymine
Show Abstract · Added March 14, 2018
Four minireviews deal with aspects of the α-ketoglutarate/iron-dependent dioxygenases in this eighth Thematic Series on Metals in Biology. The minireviews cover a general introduction and synopsis of the current understanding of mechanisms of catalysis, the roles of these dioxygenases in post-translational protein modification and de-modification, the roles of the ten-eleven translocation (Tet) dioxygenases in the modification of methylated bases (5mC, T) in DNA relevant to epigenetic mechanisms, and the roles of the AlkB-related dioxygenases in the repair of damaged DNA and RNA. The use of α-ketoglutarate (alternatively termed 2-oxoglutarate) as a co-substrate in so many oxidation reactions throughout much of nature is notable and has surprisingly emerged from biochemical and genomic analysis. About 60 of these enzymes are now recognized in humans, and a number have been identified as having critical functions.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Integrated compensatory network is activated in the absence of NCC phosphorylation.
Grimm PR, Lazo-Fernandez Y, Delpire E, Wall SM, Dorsey SG, Weinman EJ, Coleman R, Wade JB, Welling PA
(2015) J Clin Invest 125: 2136-50
MeSH Terms: Amiloride, Ammonia, Animals, Biological Transport, Blood Pressure, Carbonic Anhydrases, Chlorides, Disease Models, Animal, Enzyme Activation, Epithelial Sodium Channels, Gene Expression Profiling, Gene Regulatory Networks, Gitelman Syndrome, Ketoglutaric Acids, Kidney Glomerulus, Male, Mice, Mice, Knockout, Natriuresis, Nephrons, Paracrine Communication, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Receptors, Notch, Receptors, Purinergic P2, Renal Reabsorption, Signal Transduction, Sodium Chloride, Sodium-Potassium-Chloride Symporters, Solute Carrier Family 12, Member 3
Show Abstract · Added May 3, 2017
Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.
0 Communities
1 Members
0 Resources
31 MeSH Terms
Anaplerotic input is sufficient to induce time-dependent potentiation of insulin release in rat pancreatic islets.
Gunawardana SC, Liu YJ, Macdonald MJ, Straub SG, Sharp GW
(2004) Am J Physiol Endocrinol Metab 287: E828-33
MeSH Terms: Acetyl Coenzyme A, Amino Acids, Amino Acids, Cyclic, Analysis of Variance, Animals, Calcium, Citric Acid Cycle, Enzyme Activation, Glucose, In Vitro Techniques, Insulin, Insulin Secretion, Islets of Langerhans, Ketoglutaric Acids, Male, Mitochondria, Rats, Rats, Wistar, Signal Transduction, Stimulation, Chemical, Up-Regulation
Show Abstract · Added November 1, 2012
Nutrients that induce biphasic insulin release, such as glucose and leucine, provide acetyl-CoA and anaplerotic input in the beta-cell. The first phase of release requires increased ATP production leading to increased intracellular Ca(2+) concentration ([Ca(2+)](i)). The second phase requires increased [Ca(2+)](i) and anaplerosis. There is strong evidence to indicate that the second phase is due to augmentation of Ca(2+)-stimulated release via the K(ATP) channel-independent pathway. To test whether the phenomenon of time-dependent potentiation (TDP) has similar properties to the ATP-sensitive K(+) channel-independent pathway, we monitored the ability of different agents that provide acetyl-CoA and anaplerotic input or both of these inputs to induce TDP. The results show that anaplerotic input is sufficient to induce TDP. Interestingly, among the agents tested, the nonsecretagogue glutamine, the nonhydrolyzable analog of leucine aminobicyclo[2.2.1]heptane-2-carboxylic acid, and succinic acid methyl ester all induced TDP, and all significantly increased alpha-ketoglutarate levels in the islets. In conclusion, anaplerosis that enhances the supply and utilization of alpha-ketoglutarate in the tricarboxylic acid cycle appears to play an essential role in the generation of TDP.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Ca2+-dependent activation of the malate-aspartate shuttle by norepinephrine and vasopressin in perfused rat liver.
Sugano T, Nishimura K, Sogabe N, Shiota M, Oyama N, Noda S, Ohta M
(1988) Arch Biochem Biophys 264: 144-54
MeSH Terms: Alanine, Animals, Asparagine, Aspartic Acid, Calcimycin, Calcium, Ethanol, Glucose, Glutamates, Glutamic Acid, Ketoglutaric Acids, Liver, Malates, Male, Norepinephrine, Perfusion, Rats, Rats, Inbred Strains, Sorbitol, Vasopressins
Show Abstract · Added December 10, 2013
The role of Ca2+ in stimulation of the malate-aspartate shuttle by norepinephrine and vasopressin was studied in perfused rat liver. Shuttle capacity was indexed by measuring the changes in both the rate of production of glucose from sorbitol and the ratio of lactate to pyruvate during the oxidation of ethanol. (T. Sugano et al. (1986) Amer. J. Physiol. 251, E385-E392). Asparagine (0.5 mM), but not alanine (0.5 mM) decreased the ethanol-induced responses. Norepinephrine and vasopressin had no effect on the ethanol-induced responses when the liver was perfused with sorbitol or glycerol. In the presence of 0.25 mM alanine, norepinephrine, vasopressin, and A23187 decreased the ethanol-induced responses that occurred with the increase of flux of Ca2+. In liver perfused with Ca2+-free medium, asparagine also decreased the ethanol-induced responses, but norepinephrine and vasopressin had no effect. Aminooxyacetate inhibited the effects of norepinephrine, A23187, and asparagine. Regardless of the presence or absence of perfusate Ca2+, the combination of glucagon and alanine had no effect on the ethanol-induced responses. Norepinephrine caused a decrease in levels of alpha-ketoglutarate, aspartate, and glutamate in hepatocytes incubated with Ca2+. The present data suggest that the redistribution of cellular Ca2+ may activate the efflux of aspartate from mitochondria in rat liver, resulting in an increase in the capacity of the malate-aspartate shuttle.
0 Communities
1 Members
0 Resources
20 MeSH Terms