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Article: Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice
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TitlePyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice
 
AuthorsMoriyama, M3
Li, MX1
Kobayashi, K1
Sinasac, DS4
Kannan, Y3
Iijima, M1
Horiuchi, M1
Tsui, LC4
Tanaka, M2
Nakamura, Y3
Saheki, T1
 
KeywordsAdult-onset type II citrullinemia
Argininosuccinate synthetase
Citrin deficiency
Hyperammonemia
Pyruvate
Redox state
Ureogenesis
 
Issue Date2006
 
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
 
CitationJournal Of Hepatology, 2006, v. 44 n. 5, p. 930-938 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.jhep.2005.09.018
 
AbstractBackground/Aims: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn-/-) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn-/- liver. Methods: We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system. Results: Pyruvate infusion lowered the L/P ratio and corrected the deficit in ureogenesis in the Ctrn-/- liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn-/- liver and led to a fall in the L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P ratio in the Ctrn-/- liver. Conclusions: Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD+ ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients. © 2005 European Association for the Study of the Liver.
 
ISSN0168-8278
2012 Impact Factor: 9.858
2012 SCImago Journal Rankings: 2.797
 
DOIhttp://dx.doi.org/10.1016/j.jhep.2005.09.018
 
ISI Accession Number IDWOS:000237327800014
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorMoriyama, M
 
dc.contributor.authorLi, MX
 
dc.contributor.authorKobayashi, K
 
dc.contributor.authorSinasac, DS
 
dc.contributor.authorKannan, Y
 
dc.contributor.authorIijima, M
 
dc.contributor.authorHoriuchi, M
 
dc.contributor.authorTsui, LC
 
dc.contributor.authorTanaka, M
 
dc.contributor.authorNakamura, Y
 
dc.contributor.authorSaheki, T
 
dc.date.accessioned2011-12-15T03:39:30Z
 
dc.date.available2011-12-15T03:39:30Z
 
dc.date.issued2006
 
dc.description.abstractBackground/Aims: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn-/-) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn-/- liver. Methods: We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system. Results: Pyruvate infusion lowered the L/P ratio and corrected the deficit in ureogenesis in the Ctrn-/- liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn-/- liver and led to a fall in the L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P ratio in the Ctrn-/- liver. Conclusions: Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD+ ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients. © 2005 European Association for the Study of the Liver.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Hepatology, 2006, v. 44 n. 5, p. 930-938 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.jhep.2005.09.018
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.jhep.2005.09.018
 
dc.identifier.epage938
 
dc.identifier.isiWOS:000237327800014
 
dc.identifier.issn0168-8278
2012 Impact Factor: 9.858
2012 SCImago Journal Rankings: 2.797
 
dc.identifier.issue5
 
dc.identifier.openurl
 
dc.identifier.pmid16458993
 
dc.identifier.scopuseid_2-s2.0-33645810180
 
dc.identifier.spage930
 
dc.identifier.urihttp://hdl.handle.net/10722/143607
 
dc.identifier.volume44
 
dc.languageeng
 
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
 
dc.publisher.placeNetherlands
 
dc.relation.ispartofJournal of Hepatology
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAmmonia - metabolism
 
dc.subject.meshCalcium-Binding Proteins - genetics
 
dc.subject.meshCitrullinemia - drug therapy - genetics - metabolism
 
dc.subject.meshOrganic Anion Transporters - genetics
 
dc.subject.meshPyruvic Acid - pharmacology
 
dc.subjectAdult-onset type II citrullinemia
 
dc.subjectArgininosuccinate synthetase
 
dc.subjectCitrin deficiency
 
dc.subjectHyperammonemia
 
dc.subjectPyruvate
 
dc.subjectRedox state
 
dc.subjectUreogenesis
 
dc.titlePyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice
 
dc.typeArticle
 
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<contributor.author>Kannan, Y</contributor.author>
<contributor.author>Iijima, M</contributor.author>
<contributor.author>Horiuchi, M</contributor.author>
<contributor.author>Tsui, LC</contributor.author>
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<description.abstract>Background/Aims: Mutations in SLC25A13, encoding the mitochondrial aspartate-glutamate carrier citrin, cause adult-onset type II citrullinemia (CTLN2) in humans. We have previously reported that although citrin-knockout (Ctrn-/-) mice fail to display symptoms of CTLN2, liver perfusion revealed a deficit in ureogenesis from ammonia accompanied by an increase in the perfusate lactate-to-pyruvate (L/P) ratio. The present study explores the effects of pyruvate, aspartate and citrate on improving the abnormalities observed in the Ctrn-/- liver. Methods: We measured the rate of ureogenesis from ammonium chloride using the liver-perfusion system. Results: Pyruvate infusion lowered the L/P ratio and corrected the deficit in ureogenesis in the Ctrn-/- liver. This effect was found to be dose-dependent in both instances. Phenazine methosulfate, a cytosolic oxidant, also improved the rate of ureogenesis in the Ctrn-/- liver and led to a fall in the L/P ratio. The addition of aspartate or citrate did not change either the rate of ureogenesis or the L/P ratio in the Ctrn-/- liver. Conclusions: Citrin deficiency disturbs urea synthesis primarily as a result of an elevated cytosolic NADH/NAD+ ratio owing to limited reoxidation of reducing equivalents. Clinically, pyruvate may have a therapeutic benefit for CTLN2 patients. &#169; 2005 European Association for the Study of the Liver.</description.abstract>
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Author Affiliations
  1. Kagoshima University Faculty of Medicine
  2. Tokyo Metropolitan Institute of Gerontology
  3. Osaka Prefecture University
  4. Hospital for Sick Children University of Toronto