File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency

TitleCitrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency
Authors
Issue Date2007
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2007, v. 282 n. 34, p. 25041-25052 How to Cite?
AbstractCitrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol.Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. Anincreased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD + ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/143105
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorSaheki, Ten_HK
dc.contributor.authorIijima, Men_HK
dc.contributor.authorMeng, XLen_HK
dc.contributor.authorKobayashi, Ken_HK
dc.contributor.authorHoriuchi, Men_HK
dc.contributor.authorUshikai, Men_HK
dc.contributor.authorOkumura, Fen_HK
dc.contributor.authorXiao, JMen_HK
dc.contributor.authorInoue, Ien_HK
dc.contributor.authorTajima, Aen_HK
dc.contributor.authorMoriyama, Men_HK
dc.contributor.authorEto, Ken_HK
dc.contributor.authorKadowaki, Ten_HK
dc.contributor.authorSinasac, DSen_HK
dc.contributor.authorTsui, LCen_HK
dc.contributor.authorTsuji, Men_HK
dc.contributor.authorOkano, Aen_HK
dc.contributor.authorKobayashi, Ten_HK
dc.date.accessioned2011-10-31T04:49:54Z-
dc.date.available2011-10-31T04:49:54Z-
dc.date.issued2007en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2007, v. 282 n. 34, p. 25041-25052en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143105-
dc.description.abstractCitrin is the liver-type mitochondrial aspartate-glutamate carrier that participates in urea, protein, and nucleotide biosynthetic pathways by supplying aspartate from mitochondria to the cytosol.Citrin also plays a role in transporting cytosolic NADH reducing equivalents into mitochondria as a component of the malate-aspartate shuttle. In humans, loss-of-function mutations in the SLC25A13 gene encoding citrin cause both adult-onset type II citrullinemia and neonatal intrahepatic cholestasis, collectively referred to as human citrin deficiency. Citrin knock-out mice fail to display features of human citrin deficiency. Based on the hypothesis that an enhanced glycerol phosphate shuttle activity may be compensating for the loss of citrin function in the mouse, we have generated mice with a combined disruption of the genes for citrin and mitochondrial glycerol 3-phosphate dehydrogenase. The resulting double knock-out mice demonstrated citrullinemia, hyperammonemia that was further elevated by oral sucrose administration, hypoglycemia, and a fatty liver, all features of human citrin deficiency. Anincreased hepatic lactate/pyruvate ratio in the double knock-out mice compared with controls was also further elevated by the oral sucrose administration, suggesting that an altered cytosolic NADH/NAD + ratio is closely associated with the hyperammonemia observed. Microarray analyses identified over 100 genes that were differentially expressed in the double knock-out mice compared with wild-type controls, revealing genes potentially involved in compensatory or downstream effects of the combined mutations. Together, our data indicate that the more severe phenotype present in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice represents a more accurate model of human citrin deficiency than citrin knock-out mice. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.en_HK
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.-
dc.subject.meshCalcium-Binding Proteins - deficiency - genetics - physiology-
dc.subject.meshGlycerol - chemistry-
dc.subject.meshGlycerolphosphate Dehydrogenase - genetics-
dc.subject.meshMitochondria - enzymology - genetics-
dc.subject.meshOrganic Anion Transporters - deficiency - genetics - physiology-
dc.titleCitrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiencyen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0021-9258&volume=282&issue=34&spage=25041&epage=25052&date=2007&atitle=Citrin/mitochondrial+glycerol-3-phosphate+dehydrogenase+double+knock-out+mice+recapitulate+features+of+human+citrin+deficiency-
dc.identifier.emailTsui, LC: tsuilc@hkucc.hku.hken_HK
dc.identifier.authorityTsui, LC=rp00058en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1074/jbc.M702031200en_HK
dc.identifier.pmid17591776-
dc.identifier.scopuseid_2-s2.0-34548337267en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34548337267&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume282en_HK
dc.identifier.issue34en_HK
dc.identifier.spage25041en_HK
dc.identifier.epage25052en_HK
dc.identifier.isiWOS:000248933000060-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSaheki, T=7005678417en_HK
dc.identifier.scopusauthoridIijima, M=7201773787en_HK
dc.identifier.scopusauthoridMeng, XL=35080845200en_HK
dc.identifier.scopusauthoridKobayashi, K=7407127141en_HK
dc.identifier.scopusauthoridHoriuchi, M=7202777818en_HK
dc.identifier.scopusauthoridUshikai, M=9734292400en_HK
dc.identifier.scopusauthoridOkumura, F=36641598200en_HK
dc.identifier.scopusauthoridXiao, JM=35081515700en_HK
dc.identifier.scopusauthoridInoue, I=7201971017en_HK
dc.identifier.scopusauthoridTajima, A=54970692400en_HK
dc.identifier.scopusauthoridMoriyama, M=7201454259en_HK
dc.identifier.scopusauthoridEto, K=7101682279en_HK
dc.identifier.scopusauthoridKadowaki, T=35371466600en_HK
dc.identifier.scopusauthoridSinasac, DS=7801388288en_HK
dc.identifier.scopusauthoridTsui, LC=7102754167en_HK
dc.identifier.scopusauthoridTsuji, M=35081306400en_HK
dc.identifier.scopusauthoridOkano, A=35854189400en_HK
dc.identifier.scopusauthoridKobayashi, T=7406708579en_HK

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats