title: 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.
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.
authors.affiliation: Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Izumisano, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Moriyama
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan; Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujimoto
authors.affiliation: Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Rikimaru
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Department of Hygiene and Health Promotion Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Miharu
authors.initials: M
authors.lastname: Ushikai
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Eishi
authors.initials: E
authors.lastname: Kuroda
authors.affiliation: Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Izumisano, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawabe
authors.affiliation: Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Izumisano, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Takano
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Asakawa
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Inui
authors.affiliation: Department of Internal Medicine, Teikyo University, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Alberta, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Sinasac
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Japan; Okano Children's Clinic, Izumi, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Okano
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Yazaki
authors.affiliation: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Research Development, MILS International, Kanazawa, Japan.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China.
authors.forename: Yuan-Zong
authors.initials: YZ
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sakamoto
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Neonatology, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsubuchi
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Endo
authors.affiliation: Department of Hygiene and Health Promotion Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Horiuchi
authors.affiliation: Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Izumisano, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan; Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan.
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
keywords: Citrin deficiency; Glycerol; Glycerol 3-phosphate; Mitochondrial aspartate-glutamate carrier; Pyruvate; Redox state