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CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.
Cappel DA, Lantier L, Palmisano BT, Wasserman DH, Stafford JM
(2015) PLoS One 10: e0136915
MeSH Terms: Animals, Cholesterol Ester Transfer Proteins, Diet, High-Fat, Female, Gene Expression Regulation, Glutamic Acid, Humans, Malates, Mice, Mitochondria, Muscle, Obesity, Oxidation-Reduction, Physical Conditioning, Animal
Show Abstract · Added September 28, 2015
Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.
1 Communities
4 Members
0 Resources
13 MeSH Terms
Nox2-induced production of mitochondrial superoxide in angiotensin II-mediated endothelial oxidative stress and hypertension.
Dikalov SI, Nazarewicz RR, Bikineyeva A, Hilenski L, Lassègue B, Griendling KK, Harrison DG, Dikalova AE
(2014) Antioxid Redox Signal 20: 281-94
MeSH Terms: Angiotensin II, Animals, CSK Tyrosine-Protein Kinase, Cyclic N-Oxides, Cytoplasm, Disease Models, Animal, Electron Transport, Endothelial Cells, Gene Silencing, Humans, Hydrogen Peroxide, Hypertension, Malates, Membrane Glycoproteins, Mice, Mice, Knockout, Mitochondria, Heart, NADPH Oxidase 2, NADPH Oxidases, Oxidative Stress, Protein Isoforms, Protein Transport, RNA Interference, Reactive Oxygen Species, Superoxides, src-Family Kinases
Show Abstract · Added March 30, 2014
AIMS - Angiotensin II (AngII)-induced superoxide (O2(•-)) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2(•-) and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension.
RESULTS - Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2(•-) production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2(•-) and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2(•-) production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK(+)ATP) with 5-hydroxydecanoic acid or specific PKCɛ peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2(•-). The mitoK(+)ATP agonist diazoxide increased mitochondrial O2(•-), cytoplasmic c-Src phosphorylation and cytoplasmic O2(•-) suggesting feed-forward regulation of cellular O2(•-) by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2(•-), diminished aortic H2O2, and reduced blood pressure in hypertensive mice.
INNOVATION AND CONCLUSIONS - These studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2(•-) and reverse electron transfer may represent new pharmacological targets for the treatment of hypertension.
1 Communities
4 Members
0 Resources
26 MeSH Terms
Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV
(2012) Cell Metab 15: 110-21
MeSH Terms: B-Lymphocytes, Carbon Isotopes, Cell Hypoxia, Cell Line, Tumor, Cell Proliferation, Cell Survival, Citric Acid, Citric Acid Cycle, Fumarates, Glucose, Glutaminase, Glutamine, Humans, Isotope Labeling, Malates, Oxidation-Reduction, Sulfides, Thiadiazoles
Show Abstract · Added March 12, 2014
Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.
Copyright © 2012 Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
18 MeSH Terms
Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia.
Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P
(2002) J Neurosci 22: 2718-29
MeSH Terms: Adult, Aged, Alanine, Animals, Antipsychotic Agents, Aspartic Acid, Biogenic Polyamines, Female, Gene Expression, Gene Expression Profiling, Haloperidol, Humans, In Situ Hybridization, Logistic Models, Macaca fascicularis, Malates, Male, Middle Aged, Mitochondria, Oligonucleotide Array Sequence Analysis, Ornithine, Prefrontal Cortex, Schizophrenia, Ubiquitin
Show Abstract · Added February 12, 2015
Dysfunction of the dorsal prefrontal cortex (PFC) in schizophrenia may be associated with alterations in the regulation of brain metabolism. To determine whether abnormal expression of genes encoding proteins involved in cellular metabolism contributes to this dysfunction, we used cDNA microarrays to perform gene expression profiling of all major metabolic pathways in postmortem samples of PFC area 9 from 10 subjects with schizophrenia and 10 matched control subjects. Genes comprising 71 metabolic pathways were assessed in each pair, and only five pathways showed consistent changes (decreases) in subjects with schizophrenia. Reductions in expression were identified for genes involved in the regulation of ornithine and polyamine metabolism, the mitochondrial malate shuttle system, the transcarboxylic acid cycle, aspartate and alanine metabolism, and ubiquitin metabolism. Interestingly, although most of the metabolic genes that were consistently decreased across subjects with schizophrenia were not similarly decreased in haloperidol-treated monkeys, the transcript encoding the cytosolic form of malate dehydrogenase displayed prominent drug-associated increases in expression compared with untreated animals. These molecular analyses implicate a highly specific pattern of metabolic alterations in the PFC of subjects with schizophrenia and raise the possibility that antipsychotic medications may exert a therapeutic effect, in part, by normalizing some of these changes.
0 Communities
1 Members
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24 MeSH Terms
The capacity of the malate-aspartate shuttle differs between periportal and perivenous hepatocytes from rats.
Shiota M, Hiramatsu M, Fujimoto Y, Moriyama M, Kimura K, Ohta M, Sugano T
(1994) Arch Biochem Biophys 308: 349-56
MeSH Terms: Alanine, Alanine Transaminase, Animals, Aspartate Aminotransferases, Aspartic Acid, Cells, Cultured, Ethanol, Glucose, Glutamine, Kinetics, L-Lactate Dehydrogenase, Liver, Malate Dehydrogenase, Malates, Male, Methylphenazonium Methosulfate, Mitochondria, Liver, Portal System, Portal Vein, Pyruvate Kinase, Rats, Rats, Sprague-Dawley, Sorbitol
Show Abstract · Added December 10, 2013
The capacity of the malate-aspartate shuttle was evaluated in periportal (PP-H) and perivenous subfraction of rat hepatocytes (PV-H). The rate of glutamine production from alanine was 34-fold higher in PV-H than in PP-H. Statistically significant differences between PP-H and PV-H were found for the activities of lactate dehydrogenase and pyruvate kinase but not for the activities of NAD(+)-malate dehydrogenase, aspartate aminotransferase, and mitochondrial alanine aminotransferase. The rate of glucose production from sorbitol and the rate of ethanol utilization were higher in PP-H than in PV-H. In the presence of phenazine methosulfate (PMS), the increments in these rates were significantly greater in PV-H than in PP-H. The capacity of malate-aspartate shuttle in the presence of alanine was significantly higher in PP-H than in PV-H but in the presence of asparagine was similar in PP-H and PV-H. The results suggest that the capacity of malate-aspartate shuttle distributes heterogeneously along liver lobules with the dominance in periportal zone and that the difference of the capacity may result from the difference in the transport of aspartate across the mitochondrial membrane.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Carbon assimilation pathways during growth of Pseudomonas AM1 on methylamine and Pseudomonas MS on methylamine and trimethylsulphonium salts.
Wagner C, Quayle JR
(1972) J Gen Microbiol 72: 485-91
MeSH Terms: Alcohol Oxidoreductases, Alkanesulfonates, Aspartic Acid, Autoradiography, Carbon, Carbon Isotopes, Carboxy-Lyases, Chromatography, Fumarates, Glutamate-Ammonia Ligase, Glutamates, Glycine, Ligases, Malates, Methylamines, Methyltransferases, Pseudomonas, Serine, Succinates
Added January 20, 2015
0 Communities
1 Members
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19 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
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20 MeSH Terms
Enzymes involved in the assimilation of one-carbon units by Pseudomonas MS.
Wagner C, Levitch ME
(1975) J Bacteriol 122: 905-10
MeSH Terms: Acetates, Alcohol Oxidoreductases, Carbon, Cell-Free System, Glycine Hydroxymethyltransferase, Hydrogen-Ion Concentration, Isocitrates, Lyases, Malates, Methylamines, Methylnitronitrosoguanidine, Models, Biological, Mutagens, Mutation, Oxo-Acid-Lyases, Phosphoenolpyruvate Carboxykinase (GTP), Pseudomonas, Pyruvates, Soil Microbiology, Transferases
Show Abstract · Added January 20, 2015
Pseudomonas MS can grow on methylamine and a number of other compounds containing C1 units as a sole source of carbon and energy. Assimilation of carbon into cell material occurs via the "serine pathway" since enzymes of this pathway are induced after growth on methylamine, but not malate or acetate. A mutant has been isolated which is unable to grow on methylamine or any other related substrate providing C1 units. This mutant is also unable to grow on acetate. Measurment of enzyme activities in cell-free extracts of wild-type cells showed that growth on methylamine caused induction of isocitrate lyase, a key enzyme in the glyoxylate cycle. The mutant organism lacks malate lyase, a key enzyme of the serine pathway, and isocitrate lyase as well. These results suggest that utilization of C1 units by Pseudomonas MS results in the net accumulation of acetate which is then assimilated into cell material via the glyoxylate cycle.
0 Communities
1 Members
0 Resources
20 MeSH Terms