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TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.
Fernández-Álvarez S, Gutiérrez-de Juan V, Zubiete-Franco I, Barbier-Torres L, Lahoz A, Parés A, Luka Z, Wagner C, Lu SC, Mato JM, Martínez-Chantar ML, Beraza N
(2015) Lab Invest 95: 223-36
MeSH Terms: Amino Acid Metabolism, Inborn Errors, Animals, Bile Ducts, Blotting, Western, End Stage Liver Disease, Flow Cytometry, Glycine N-Methyltransferase, Humans, Immunohistochemistry, Killer Cells, Natural, Ligation, Mice, Mice, Knockout, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand
Show Abstract · Added January 20, 2015
Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Cirrhotic patients show low expression of GNMT that is absent in hepatocellular carcinoma (HCC) samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis, and HCC. Lack of GNMT triggers NK cell activation in GNMT(-/-) mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL(-/-)/GNMT(-/-) mice in which we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT(-/-) and TRAIL(-/-)/GNMT(-/-) mice. In GNMT(-/-) mice, exacerbated fibrogenic response after BDL concurred with NK1.1(+) cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT(-/-) mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL(-/-)/GNMT(-/-) mice showed significantly less fibrosis after BDL than GNMT(-/-) mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT(-/-) mice. Finally, in vivo silencing of DR5 efficiently protected GNMT(-/-) mice from BDL-liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.
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15 MeSH Terms
Glycine N-methyltransferase expression in the hippocampus and its role in neurogenesis and cognitive performance.
Carrasco M, Rabaneda LG, Murillo-Carretero M, Ortega-Martínez S, Martínez-Chantar ML, Woodhoo A, Luka Z, Wagner C, Lu SC, Mato JM, Micó JA, Castro C
(2014) Hippocampus 24: 840-52
MeSH Terms: Amino Acid Metabolism, Inborn Errors, Animals, Cognition, Cyclin E, Fibroblast Growth Factor 2, Gene Expression Regulation, Glycine N-Methyltransferase, Hippocampus, MAP Kinase Signaling System, Maze Learning, Memory Disorders, Methionine, Methionine Adenosyltransferase, Methylation, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Tissue Proteins, Neurogenesis, Neuronal Plasticity, Rotarod Performance Test, S-Adenosylmethionine
Show Abstract · Added January 20, 2015
The hippocampus is a brain area characterized by its high plasticity, observed at all levels of organization: molecular, synaptic, and cellular, the latter referring to the capacity of neural precursors within the hippocampus to give rise to new neurons throughout life. Recent findings suggest that promoter methylation is a plastic process subjected to regulation, and this plasticity seems to be particularly important for hippocampal neurogenesis. We have detected the enzyme GNMT (a liver metabolic enzyme) in the hippocampus. GNMT regulates intracellular levels of SAMe, which is a universal methyl donor implied in almost all methylation reactions and, thus, of prime importance for DNA methylation. In addition, we show that deficiency of this enzyme in mice (Gnmt-/-) results in high SAMe levels within the hippocampus, reduced neurogenic capacity, and spatial learning and memory impairment. In vitro, SAMe inhibited neural precursor cell division in a concentration-dependent manner, but only when proliferation signals were triggered by bFGF. Indeed, SAMe inhibited the bFGF-stimulated MAP kinase signaling cascade, resulting in decreased cyclin E expression. These results suggest that alterations in the concentration of SAMe impair neurogenesis and contribute to cognitive decline.
© 2014 Wiley Periodicals, Inc.
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22 MeSH Terms
Extracorporeal membrane oxygenation support of a severe metabolic crisis in a child with methylmalonic acidemia.
Stark RJ, Naik-Mathuria BJ, Lam FW, Olutoye OO, Sutton VR, Shekerdemian LS
(2012) ASAIO J 58: 438-9
MeSH Terms: Amino Acid Metabolism, Inborn Errors, Child, Extracorporeal Membrane Oxygenation, Female, Humans, Methylmalonic Acid, Phenotype, Respiratory Insufficiency, Treatment Outcome, Vasoplegia
Show Abstract · Added July 28, 2015
A 9-year-old female, with mut phenotype of methylmalonic acidemia who developed severe vasoplegic shock during a metabolic crisis, was successfully supported with venoarterial extracorporeal membrane oxygenation.
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10 MeSH Terms
Enzymatic activity of methionine adenosyltransferase variants identified in patients with persistent hypermethioninemia.
Fernández-Irigoyen J, Santamaría E, Chien YH, Hwu WL, Korman SH, Faghfoury H, Schulze A, Hoganson GE, Stabler SP, Allen RH, Wagner C, Mudd SH, Corrales FJ
(2010) Mol Genet Metab 101: 172-7
MeSH Terms: Acid Anhydride Hydrolases, Adult, Amino Acid Metabolism, Inborn Errors, Humans, Infant, Infant, Newborn, Isoenzymes, Male, Methionine, Methionine Adenosyltransferase
Show Abstract · Added January 20, 2015
Methionine adenosyltransferases (MAT's) are central enzymes in living organisms that have been conserved with a high degree of homology among species. In the liver, MAT I and III, tetrameric and dimeric isoforms of the same catalytic subunit encoded by the gene MAT1A, account for the predominant portion of total body synthesis of S-adenosylmethionine (SAM), a versatile sulfonium ion-containing molecule involved in a variety of vital metabolic reactions and in the control of hepatocyte proliferation and differentiation. During the past 15years 28 MAT1A mutations have been described in patients with elevated plasma methionines, total homocysteines at most only moderately elevated, and normal levels of tyrosine and other aminoacids. In this study we describe functional analyses that determine the MAT and tripolyphosphatase (PPPase) activities of 18 MAT1A variants, six of them novel, and none of them previously assayed for activity. With the exception of G69S and Y92H, all recombinant proteins showed impairment (usually severe) of MAT activity. Tripolyphosphate (PPPi) hydrolysis was decreased only in some mutant proteins but, when it was decreased MAT activity was always also impaired.
Copyright © 2010 Elsevier Inc. All rights reserved.
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10 MeSH Terms
Creatine metabolism in combined methylmalonic aciduria and homocystinuria.
Bodamer OA, Sahoo T, Beaudet AL, O'Brien WE, Bottiglieri T, Stöckler-Ipsiroglu S, Wagner C, Scaglia F
(2005) Ann Neurol 57: 557-60
MeSH Terms: Adult, Amino Acid Metabolism, Inborn Errors, Child, Child, Preschool, Creatine, Female, Glycine, Homocysteine, Homocystinuria, Humans, Male, Methionine, Methylmalonic Acid, Vitamin B 12
Show Abstract · Added January 20, 2015
Methylation is an important aspect of many fundamental biological processes including creatine biosynthesis. We studied five patients with an inborn error of cobalamin metabolism to characterize the relation between homocysteine and creatine metabolism. Plasma guanidinoacetate concentrations were increased, 14.9 +/- 4.8 micromol/L (p < 0.0001), whereas plasma creatine concentrations were in the low reference range, 43.8 +/- 20.7 micromol/L (p = not significant). Individuals with combined methylmalonic aciduria and homocystinuria have a functional impairment of the creatine synthetic pathway probably secondary to a relative depletion of labile methyl groups. The neurotoxic effects of guanidinoacetate may be partly responsible for the observed neurological phenotype.
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14 MeSH Terms
The sparse fur mouse as a model for gene therapy in ornithine carbamoyltransferase deficiency.
Batshaw ML, Yudkoff M, McLaughlin BA, Gorry E, Anegawa NJ, Smith IA, Hyman SL, Robinson MB
(1995) Gene Ther 2: 743-9
MeSH Terms: Amino Acid Metabolism, Inborn Errors, Amino Acids, Ammonia, Animals, Avoidance Learning, Crosses, Genetic, Disease Models, Animal, Female, Fertility, Genetic Therapy, Hair, Humans, Male, Mice, Mice, Mutant Strains, Ornithine Carbamoyltransferase, Ornithine Carbamoyltransferase Deficiency Disease, Orotic Acid, Pregnancy
Show Abstract · Added January 26, 2015
The sparse fur (spf/Y) mouse was evaluated as a model for studying gene therapy in ornithine carbamoyltransferase deficiency (OCTD), the most common inborn error of urea synthesis. Previous studies have defined a number of biochemical characteristics of this animal model that are analogous to the human disease: OCTD in liver, elevated ammonium and glutamine, low citrulline and arginine in plasma, elevated urinary orotic acid excretion, neurochemical alterations and responsiveness to alternative pathway therapy. In this study, metabolic flux, survival, behavior and learning of these animals were examined in preparation for a trial of gene therapy. We found that, as has been previously reported, OCT activity in liver ranged from 10 to 20% of control. Yet, stable isotope studies using 15N ammonium chloride to follow ureagenesis in vivo showed 55% of normal urea synthetic capacity. This suggests that partial correction with gene therapy may be sufficient to normalize urea synthesis. Although it has been suggested that liver OCTD and its consequent metabolic effects normalize without treatment by adulthood in the spf/Y mouse, we did not find this to be the case. We documented that the spf/Y mouse had a markedly decreased lifespan (< 10% of normal) and remained runted throughout life. In terms of behavior, the spf/Y mice had evidence of decreased learning in a passive avoidance task that was not attributable to alterations in activity. These clearly definable metabolic and behavioral abnormalities suggest that the spf/Y mouse should prove a useful model for studying the efficacy of gene therapy in OCTD.
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19 MeSH Terms