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

5 Citations (Scopus)

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 - 2015 Sep 1

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Moriyama, M., Fujimoto, Y., Rikimaru, S., Ushikai, M., Kuroda, E., Kawabe, K., Takano, K., Asakawa, A., Inui, A., Eto, K., Kadowaki, T., Sinasac, D. S., Okano, Y., Yazaki, M., Ikeda, S. I., Zhang, C., Song, Y. Z., Sakamoto, O., Kure, S., ... 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, 1852(9), 1787-1795. https://doi.org/10.1016/j.bbadis.2015.04.023