Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment

Hironori Nagasaka, Haruki Komatsu, Ayano Inui, Mariko Nakacho, Ichiro Morioka, Hirokazu Tsukahara, Shunsaku Kaji, Satoshi Hirayama, Takashi Miida, Hiroki Kondou, Kenji Ihara, Mariko Yagi, Zenro Kizaki, Kazuhiko Bessho, Takahiro Kodama, Kazumoto Iijima, Takeyori Saheki, Tohru Yorifuji, Akira Honda

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Citrin deficiency causes adult-onset type II citrullinemia (CTLN-2), which later manifests as severe liver steatosis and life-threatening encephalopathy. Long-standing energy deficit of the liver and brain may predispose ones to CTLN-2. Here, we compared the energy-driving tricarboxylic acid (TCA) cycle and fatty acid β-oxidation cycle between 22 citrin-deficient children (age, 3–13 years) with normal liver functions and 37 healthy controls (age, 5–13 years). TCA cycle analysis showed that basal plasma citrate and α-ketoglutarate levels were significantly higher in the affected than the control group (p < 0.01). Conversely, basal plasma fumarate and malate levels were significantly lower than those for the control (p < 0.001). The plasma level of 3-OH-butyrate derived from fatty acid β-oxidation was significantly higher in the affected group (p < 0.01). Ten patients underwent sodium pyruvate therapy. However, this therapy did not correct or attenuate such deviations in both cycles. Sodium pyruvate therapy significantly increased fasting insulin secretion (p < 0.01); the fasting sugar level remained unchanged. Our results suggest that citrin-deficient children show considerable deviations of TCA cycle metabolite profiles that are resistant to sodium pyruvate treatment. Thus, long-standing and considerable TCA cycle dysfunction might be a pivotal metabolic background of CTLN-2 development.

Original languageEnglish
Pages (from-to)207-212
Number of pages6
JournalMolecular Genetics and Metabolism
Volume120
Issue number3
DOIs
Publication statusPublished - Mar 1 2017
Externally publishedYes

Keywords

  • Adaptation period
  • Adult-onset type II citrullinemia
  • Citrin deficiency
  • Free fatty acid β oxidation
  • Sodium pyruvate therapy
  • Tricarboxylic acid cycle

ASJC Scopus subject areas

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

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    Nagasaka, H., Komatsu, H., Inui, A., Nakacho, M., Morioka, I., Tsukahara, H., Kaji, S., Hirayama, S., Miida, T., Kondou, H., Ihara, K., Yagi, M., Kizaki, Z., Bessho, K., Kodama, T., Iijima, K., Saheki, T., Yorifuji, T., & Honda, A. (2017). Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment. Molecular Genetics and Metabolism, 120(3), 207-212. https://doi.org/10.1016/j.ymgme.2016.12.011