title: Citrin/mitochondrial glycerol-3-phosphate dehydrogenase double knock-out mice recapitulate features of human citrin deficiency.
abstract: Citrin 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. An increased 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.
authors.affiliation: Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan. takesah@tokushima.bunri-u.ac.jp
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.forename: Mikio
authors.initials: M
authors.lastname: Iijima
authors.forename: Meng Xian
authors.initials: MX
authors.lastname: Li
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Masahisa
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Miharu
authors.initials: M
authors.lastname: Ushikai
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Okumura
authors.forename: Xiao Jian
authors.initials: XJ
authors.lastname: Meng
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Moriyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: David S
authors.initials: DS
authors.lastname: Sinasac
authors.forename: Lap-Chee
authors.initials: LC
authors.lastname: Tsui
authors.forename: Mihoko
authors.initials: M
authors.lastname: Tsuji
authors.forename: Akira
authors.initials: A
authors.lastname: Okano
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D005990:Glycerol / Q000737:chemistry; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D027361:Organic Anion Transporters / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D010710:Phosphates / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; D010710:Phosphates; C119629:SLC25A13 protein, human; C008822:citrin; D005993:Glycerolphosphate Dehydrogenase; D005990:Glycerol