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A Metabolic Basis for Endothelial-to-Mesenchymal Transition.
Xiong J, Kawagishi H, Yan Y, Liu J, Wells QS, Edmunds LR, Fergusson MM, Yu ZX, Rovira II, Brittain EL, Wolfgang MJ, Jurczak MJ, Fessel JP, Finkel T
(2018) Mol Cell 69: 689-698.e7
MeSH Terms: 3-Hydroxyacyl CoA Dehydrogenases, Acetyl Coenzyme A, Acetyl-CoA C-Acyltransferase, Animals, Carbon-Carbon Double Bond Isomerases, Carnitine O-Palmitoyltransferase, Cells, Cultured, Endothelium, Vascular, Enoyl-CoA Hydratase, Epithelial-Mesenchymal Transition, Fatty Acids, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidation-Reduction, Racemases and Epimerases, Signal Transduction, Transforming Growth Factor beta
Show Abstract · Added March 14, 2018
Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2 mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
20 MeSH Terms
Acetate dependence of tumors.
Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, Walters H, Tantawy MN, Fu A, Manning HC, Horton JD, Hammer RE, McKnight SL, Tu BP
(2014) Cell 159: 1591-602
MeSH Terms: Acetate-CoA Ligase, Acetates, Acetyl Coenzyme A, Animals, Humans, Immunohistochemistry, Liver Neoplasms, Mice, Neoplasms, Positron-Emission Tomography, Triple Negative Breast Neoplasms
Show Abstract · Added January 23, 2015
Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors.
Copyright © 2014 Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
11 MeSH Terms
Acyl-coenzyme A-binding protein regulates Beta-oxidation required for growth and survival of non-small cell lung cancer.
Harris FT, Rahman SM, Hassanein M, Qian J, Hoeksema MD, Chen H, Eisenberg R, Chaurand P, Caprioli RM, Shiota M, Massion PP
(2014) Cancer Prev Res (Phila) 7: 748-57
MeSH Terms: Acetyl Coenzyme A, Adenocarcinoma, Adenosine Triphosphate, Apoptosis, Blotting, Western, Bronchi, Carcinoma in Situ, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Proliferation, Cells, Cultured, Diazepam Binding Inhibitor, Humans, Immunoenzyme Techniques, Lung Neoplasms, Membrane Potential, Mitochondrial, Oxidation-Reduction, Palmitic Acid, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added May 20, 2014
We identified acyl-coenzyme A-binding protein (ACBP) as part of a proteomic signature predicting the risk of having lung cancer. Because ACBP is known to regulate β-oxidation, which in turn controls cellular proliferation, we hypothesized that ACBP contributes to regulation of cellular proliferation and survival of non-small cell lung cancer (NSCLC) by modulating β-oxidation. We used matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) and immunohistochemistry (IHC) to confirm the tissue localization of ABCP in pre-invasive and invasive NSCLCs. We correlated ACBP gene expression levels in NSCLCs with clinical outcomes. In loss-of-function studies, we tested the effect of the downregulation of ACBP on cellular proliferation and apoptosis in normal bronchial and NSCLC cell lines. Using tritiated-palmitate ((3)H-palmitate), we measured β-oxidation levels and tested the effect of etomoxir, a β-oxidation inhibitor, on proliferation and apoptosis. MALDI-IMS and IHC analysis confirmed that ACBP is overexpressed in pre-invasive and invasive lung cancers. High ACBP gene expression levels in NSCLCs correlated with worse survival (HR = 1.73). We observed a 40% decrease in β-oxidation and concordant decreases in proliferation and increases in apoptosis in ACBP-depleted NSCLC cells as compared with bronchial airway epithelial cells. Inhibition of β-oxidation by etomoxir in ACBP-overexpressing cells produced dose-dependent decrease in proliferation and increase in apoptosis (P = 0.01 and P < 0.001, respectively). These data suggest a role for ACBP in controlling lung cancer progression by regulating β-oxidation.
©2014 American Association for Cancer Research.
1 Communities
5 Members
0 Resources
19 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
The effect of sodium butyrate on histone modification.
Sealy L, Chalkley R
(1978) Cell 14: 115-21
MeSH Terms: Acetates, Acetyl Coenzyme A, Acetylation, Amidohydrolases, Butyrates, Cell Line, Cycloheximide, Histone Deacetylase Inhibitors, Histones, Propionates
Show Abstract · Added March 5, 2014
The hyperacetylation of histones due to treatment of cultured cells with sodium butyrate has been studied. The hyperacetylation is due to inhibition of histone deacetylase. Other short chain fatty acids including acetic, isobutyric and propionic acid also produce increased modification. Histone H4 already deposited on the chromosome can be rapidly acetylated to the extent of about 70%. That 80% of histone H4 is acetylated after a 24 hr exposure to butyrate is due to the fact that incoming H4 histone is 100% acetylated and does not return to the parental unmodified form in the presence of butyrate.
0 Communities
1 Members
0 Resources
10 MeSH Terms