Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency

Mitsuaki Moriyama, Yuki Fujimoto, Shizuka Rikimaru, Miharu Ushikai, Eishi Kuroda, Kenji Kawabe, Katsura Takano, Akihiro Asakawa, Akio Inui, Kazuhiro Eto, Takashi Kadowaki, David S. Sinasac, Yoshiyuki Okano, Masahide Yazaki, Shu ichi Ikeda, Chunhua Zhang, Yuan Zong Song, Osamu Sakamoto, Shigeo Kure, Hiroshi MitsubuchiFumio Endo, Masahisa Horiuchi, Yoichi Nakamura, Ken ichi Yamamura, Takeyori Saheki

Research output: Contribution to journalArticle

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Abstract

The mitochondrial aspartate-glutamate carrier isoform 2 (citrin) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse has been a useful model of human citrin deficiency. One of the most prominent findings has been markedly increased hepatic glycerol 3-phosphate (G3P) following oral administration of a sucrose solution. We aimed to investigate whether this change is detectable outside of the liver, and to explore the mechanism underlying the increased hepatic G3P in these mice. We measured G3P and its metabolite glycerol in plasma and urine of the mice under various conditions. Glycerol synthesis from fructose was also studied using the liver perfusion system. The citrin/mGPD double-knockout mice showed increased urine G3P and glycerol under normal, fed conditions. We also found increased plasma glycerol under fasted conditions, while oral administration of different carbohydrates or ethanol led to substantially increased plasma glycerol. Fructose infusion to the perfused liver of the double-knockout mice augmented hepatic glycerol synthesis, and was accompanied by a concomitant increase in the lactate/pyruvate (L/P) ratio. Co-infusion of either pyruvate or phenazine methosulfate, a cytosolic oxidant, with fructose corrected the high L/P ratio, leading to reduced glycerol synthesis. Overall, these findings suggest that hepatic glycerol synthesis is cytosolic NADH/NAD+ ratio-dependent and reveal a likely regulatory mechanism for hepatic glycerol synthesis following a high carbohydrate load in citrin-deficient patients. Therefore, urine G3P and glycerol may represent potential diagnostic markers for human citrin deficiency.

Original languageEnglish
Pages (from-to)1787-1795
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number9
DOIs
Publication statusPublished - Sep 1 2015
Externally publishedYes

Fingerprint

Glycerolphosphate Dehydrogenase
Knockout Mice
Glycerol
Urine
Liver
Fructose
Pyruvic Acid
NAD
Oral Administration
Lactic Acid
Methylphenazonium Methosulfate
Carbohydrates
alpha-glycerophosphoric acid
citrin
Adult-onset citrullinemia type 2
Oxidants
Sucrose
Protein Isoforms
Ethanol
Perfusion

Keywords

  • Citrin deficiency
  • Glycerol
  • Glycerol 3-phosphate
  • Mitochondrial aspartate-glutamate carrier
  • Pyruvate
  • Redox state

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse : Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency. / Moriyama, Mitsuaki; Fujimoto, Yuki; Rikimaru, Shizuka; Ushikai, Miharu; Kuroda, Eishi; Kawabe, Kenji; Takano, Katsura; Asakawa, Akihiro; Inui, Akio; Eto, Kazuhiro; Kadowaki, Takashi; Sinasac, David S.; Okano, Yoshiyuki; Yazaki, Masahide; Ikeda, Shu ichi; Zhang, Chunhua; Song, Yuan Zong; Sakamoto, Osamu; Kure, Shigeo; Mitsubuchi, Hiroshi; Endo, Fumio; Horiuchi, Masahisa; Nakamura, Yoichi; Yamamura, Ken ichi; Saheki, Takeyori.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1852, No. 9, 01.09.2015, p. 1787-1795.

Research output: Contribution to journalArticle

Moriyama, M, Fujimoto, Y, Rikimaru, S, Ushikai, M, Kuroda, E, Kawabe, K, Takano, K, Asakawa, A, Inui, A, Eto, K, Kadowaki, T, Sinasac, DS, Okano, Y, Yazaki, M, Ikeda, SI, Zhang, C, Song, YZ, Sakamoto, O, Kure, S, Mitsubuchi, H, Endo, F, Horiuchi, M, Nakamura, Y, Yamamura, KI & Saheki, T 2015, 'Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1852, no. 9, pp. 1787-1795. https://doi.org/10.1016/j.bbadis.2015.04.023
Moriyama, Mitsuaki ; Fujimoto, Yuki ; Rikimaru, Shizuka ; Ushikai, Miharu ; Kuroda, Eishi ; Kawabe, Kenji ; Takano, Katsura ; Asakawa, Akihiro ; Inui, Akio ; Eto, Kazuhiro ; Kadowaki, Takashi ; Sinasac, David S. ; Okano, Yoshiyuki ; Yazaki, Masahide ; Ikeda, Shu ichi ; Zhang, Chunhua ; Song, Yuan Zong ; Sakamoto, Osamu ; Kure, Shigeo ; Mitsubuchi, Hiroshi ; Endo, Fumio ; Horiuchi, Masahisa ; Nakamura, Yoichi ; Yamamura, Ken ichi ; Saheki, Takeyori. / Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse : Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2015 ; Vol. 1852, No. 9. pp. 1787-1795.
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abstract = "The mitochondrial aspartate-glutamate carrier isoform 2 (citrin) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse has been a useful model of human citrin deficiency. One of the most prominent findings has been markedly increased hepatic glycerol 3-phosphate (G3P) following oral administration of a sucrose solution. We aimed to investigate whether this change is detectable outside of the liver, and to explore the mechanism underlying the increased hepatic G3P in these mice. We measured G3P and its metabolite glycerol in plasma and urine of the mice under various conditions. Glycerol synthesis from fructose was also studied using the liver perfusion system. The citrin/mGPD double-knockout mice showed increased urine G3P and glycerol under normal, fed conditions. We also found increased plasma glycerol under fasted conditions, while oral administration of different carbohydrates or ethanol led to substantially increased plasma glycerol. Fructose infusion to the perfused liver of the double-knockout mice augmented hepatic glycerol synthesis, and was accompanied by a concomitant increase in the lactate/pyruvate (L/P) ratio. Co-infusion of either pyruvate or phenazine methosulfate, a cytosolic oxidant, with fructose corrected the high L/P ratio, leading to reduced glycerol synthesis. Overall, these findings suggest that hepatic glycerol synthesis is cytosolic NADH/NAD+ ratio-dependent and reveal a likely regulatory mechanism for hepatic glycerol synthesis following a high carbohydrate load in citrin-deficient patients. Therefore, urine G3P and glycerol may represent potential diagnostic markers for human citrin deficiency.",
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AU - Moriyama, Mitsuaki

AU - Fujimoto, Yuki

AU - Rikimaru, Shizuka

AU - Ushikai, Miharu

AU - Kuroda, Eishi

AU - Kawabe, Kenji

AU - Takano, Katsura

AU - Asakawa, Akihiro

AU - Inui, Akio

AU - Eto, Kazuhiro

AU - Kadowaki, Takashi

AU - Sinasac, David S.

AU - Okano, Yoshiyuki

AU - Yazaki, Masahide

AU - Ikeda, Shu ichi

AU - Zhang, Chunhua

AU - Song, Yuan Zong

AU - Sakamoto, Osamu

AU - Kure, Shigeo

AU - Mitsubuchi, Hiroshi

AU - Endo, Fumio

AU - Horiuchi, Masahisa

AU - Nakamura, Yoichi

AU - Yamamura, Ken ichi

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N2 - The mitochondrial aspartate-glutamate carrier isoform 2 (citrin) and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse has been a useful model of human citrin deficiency. One of the most prominent findings has been markedly increased hepatic glycerol 3-phosphate (G3P) following oral administration of a sucrose solution. We aimed to investigate whether this change is detectable outside of the liver, and to explore the mechanism underlying the increased hepatic G3P in these mice. We measured G3P and its metabolite glycerol in plasma and urine of the mice under various conditions. Glycerol synthesis from fructose was also studied using the liver perfusion system. The citrin/mGPD double-knockout mice showed increased urine G3P and glycerol under normal, fed conditions. We also found increased plasma glycerol under fasted conditions, while oral administration of different carbohydrates or ethanol led to substantially increased plasma glycerol. Fructose infusion to the perfused liver of the double-knockout mice augmented hepatic glycerol synthesis, and was accompanied by a concomitant increase in the lactate/pyruvate (L/P) ratio. Co-infusion of either pyruvate or phenazine methosulfate, a cytosolic oxidant, with fructose corrected the high L/P ratio, leading to reduced glycerol synthesis. Overall, these findings suggest that hepatic glycerol synthesis is cytosolic NADH/NAD+ ratio-dependent and reveal a likely regulatory mechanism for hepatic glycerol synthesis following a high carbohydrate load in citrin-deficient patients. Therefore, urine G3P and glycerol may represent potential diagnostic markers for human citrin deficiency.

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