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

Fingerprint

Citric Acid Cycle
Metabolites
Pyruvic Acid
Sodium
Liver
Plasmas
Fasting
Fatty Acids
Oxidation
Fumarates
Butyrates
Brain Diseases
Fatty Liver
Therapeutics
Citric Acid
Sugars
Brain
Insulin
Control Groups
citrin

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

Cite this

Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment. / Nagasaka, Hironori; Komatsu, Haruki; Inui, Ayano; Nakacho, Mariko; Morioka, Ichiro; Tsukahara, Hirokazu; Kaji, Shunsaku; Hirayama, Satoshi; Miida, Takashi; Kondou, Hiroki; Ihara, Kenji; Yagi, Mariko; Kizaki, Zenro; Bessho, Kazuhiko; Kodama, Takahiro; Iijima, Kazumoto; Saheki, Takeyori; Yorifuji, Tohru; Honda, Akira.

In: Molecular Genetics and Metabolism, Vol. 120, No. 3, 01.03.2017, p. 207-212.

Research output: Contribution to journalArticle

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, vol. 120, no. 3, pp. 207-212. https://doi.org/10.1016/j.ymgme.2016.12.011
Nagasaka, Hironori ; Komatsu, Haruki ; Inui, Ayano ; Nakacho, Mariko ; Morioka, Ichiro ; Tsukahara, Hirokazu ; Kaji, Shunsaku ; Hirayama, Satoshi ; Miida, Takashi ; Kondou, Hiroki ; Ihara, Kenji ; Yagi, Mariko ; Kizaki, Zenro ; Bessho, Kazuhiko ; Kodama, Takahiro ; Iijima, Kazumoto ; Saheki, Takeyori ; Yorifuji, Tohru ; Honda, Akira. / Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment. In: Molecular Genetics and Metabolism. 2017 ; Vol. 120, No. 3. pp. 207-212.
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AU - Nagasaka, Hironori

AU - Komatsu, Haruki

AU - Inui, Ayano

AU - Nakacho, Mariko

AU - Morioka, Ichiro

AU - Tsukahara, Hirokazu

AU - Kaji, Shunsaku

AU - Hirayama, Satoshi

AU - Miida, Takashi

AU - Kondou, Hiroki

AU - Ihara, Kenji

AU - Yagi, Mariko

AU - Kizaki, Zenro

AU - Bessho, Kazuhiko

AU - Kodama, Takahiro

AU - Iijima, Kazumoto

AU - Saheki, Takeyori

AU - Yorifuji, Tohru

AU - Honda, Akira

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N2 - 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.

AB - 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.

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