title: Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency.
abstract: Mice carrying simultaneous homozygous mutations in the genes encoding citrin, the mitochondrial aspartate-glutamate carrier 2 (AGC2) protein, and mitochondrial glycerol-3-phosphate dehydrogenase (mGPD), are a phenotypically representative model of human citrin (a.k.a., AGC2) deficiency. In this study, we investigated the voluntary oral intake and preference for sucrose, glycerol or ethanol solutions by wild-type, citrin (Ctrn)-knockout (KO), mGPD-KO, and Ctrn/mGPD double-KO mice; all substances that are known or suspected precipitating factors in the pathogenesis of human citrin deficiency. The double-KO mice showed clear suppressed intake of sucrose, consuming less with progressively higher concentrations compared to the other mice. Similar observations were made when glycerol or ethanol were given. The preference of Ctrn-KO and mGPD-KO mice varied with the different treatments; essentially no differences were observed for sucrose, while an intermediate intake or similar to that of the double-KO mice was observed for glycerol and ethanol. We next examined the hepatic glycerol 3-phosphate, citrate, citrulline, lysine, glutamate and adenine nucleotide levels following forced enteral administration of these solutions. A strong correlation between the simultaneous increased hepatic glycerol 3-phosphate and decreased ATP or total adenine nucleotide content and observed aversion of the mice during evaluation of their voluntary preferences was found. Overall, our results suggest that the aversion observed in the double-KO mice to these solutions is initiated and/or mediated by hepatic metabolic perturbations, resulting in a behavioral response to increased hepatic cytosolic NADH and a decreased cellular adenine nucleotide pool. These findings may underlie the dietary predilections observed in human citrin deficient patients.
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan; Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan; Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan. Electronic address: takesah@gmail.com.
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.affiliation: Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Institute for Health Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ono
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujimoto
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Furuie
authors.affiliation: Laboratory of Yamamura Project, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Yamamura
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan; Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
authors.forename: Eishi
authors.initials: E
authors.lastname: Kuroda
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, Japan; Department of Hygiene and Health Promotion Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8520, 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 890-8520, 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 890-8520, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Inui
authors.affiliation: Department of Internal Medicine, Teikyo University, Tokyo 173-8605, 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 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, Izumisano 598-8531, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Moriyama
authors.affiliation: Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Alberta T2N 2N1, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Sinasac
authors.affiliation: Faculty of Health Science, Kio University, Koryo 635-0832, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Department of Molecular Metabolism and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics; D000818:Animals; D017920:Antiporters / Q000235:genetics; D020159:Citrullinemia / Q000378:metabolism*; D019422:Dietary Sucrose / Q000008:administration & dosage*; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage*; D005990:Glycerol / Q000008:administration & dosage*; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics; D005994:Glycerophosphates / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000737:chemistry*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; D019422:Dietary Sucrose; D005994:Glycerophosphates; C051046:aspartate-glutamate carrier; D000431:Ethanol; D000255:Adenosine Triphosphate; C029620:alpha-glycerophosphoric acid; D005993:Glycerolphosphate Dehydrogenase; D005990:Glycerol
keywords: ATP; Adult-onset type II citrullinemia (CTLN2); Citrin deficiency; Cytosolic NADH; Dietary aversion; Glycerol 3-phosphate