Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period

Hironori Nagasaka, Yoshiyuki Okano, Hirokazu Tsukahara, Yosuke Shigematsu, Toru Momoi, Junko Yorifuji, Takashi Miida, Toshihiro Ohura, Keiko Kobayashi, Takeyori Saheki, Kenichi Hirano, Masaki Takayanagi, Tohru Yorifuji

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) shows diverse metabolic abnormalities such as urea cycle dysfunction together with citrullinemia, galactosemia, and suppressed gluconeogenesis. Such abnormalities apparently resolve during the first year of life. However, metabolic profiles of the silent period remain unknown. We analyzed oxidative stress markers and profiles of amino acids, carbohydrates, and lipids in 20 asymptomatic children with aspartate/glutamate carrier isoform 2-citrin-deficiency aged 1-10 years, for whom tests showed normal liver function. Despite normal plasma ammonia levels, the affected children showed higher blood levels of ornithine (p < 0.001) and citrulline (p < 0.01)--amino acids involved in the urea cycle--than healthy children. Blood levels of nitrite/nitrate, metabolites of nitric oxide (NO), and asymmetric dimethylarginine inhibiting NO production from arginine were not different between these two groups. Blood glucose, galactose, pyruvate, and lactate levels after 4-5 h fasting were not different between these groups, but the affected group showed a significantly higher lactate to pyruvate ratio. Low-density and high-density lipoprotein cholesterol levels in the affected group were 1.5 times higher than those in the controls. Plasma oxidized low-density lipoprotein apparently increased in the affected children; their levels of urinary oxidative stress markers such as 8-hydroxy-2′-deoxyguanosine and acrolein-lysine were significantly higher than those in the controls. Results of this study showed, even during the silent period, sustained hypercitrullinemia, hypercholesterolemia, and augmented oxidative stress in children with citrin deficiency.

Original languageEnglish
Pages (from-to)21-26
Number of pages6
JournalMolecular Genetics and Metabolism
Volume97
Issue number1
DOIs
Publication statusPublished - May 2009
Externally publishedYes

Keywords

  • Adult-onset type II citrullinemia
  • Amino acids
  • Aspartate/glutamate carrier isoform 2-citrin
  • Carbohydrates
  • Hypercholesterolemia
  • Neonatal intrahepatic cholestasis caused by citrin deficiency
  • Oxidative stress
  • Silent period

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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