title: Effects of supplementation on food intake, body weight and hepatic metabolites in the citrin/mitochondrial glycerol-3-phosphate dehydrogenase double-knockout mouse model of human citrin deficiency.
abstract: The C57BL/6:Slc23a13(-/-);Gpd2(-/-) double-knockout (a.k.a., citrin/mitochondrial glycerol 3-phosphate dehydrogenase double knockout or Ctrn/mGPD-KO) mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2), making it a suitable model of human citrin deficiency. In the present study, we show that when mature Ctrn/mGPD-KO mice are switched from a standard chow diet (CE-2) to a purified maintenance diet (AIN-93M), this resulted in a significant loss of body weight as a result of reduced food intake compared to littermate mGPD-KO mice. However, supplementation of the purified maintenance diet with additional protein (from 14% to 22%; and concomitant reduction or corn starch), or with specific supplementation with alanine, sodium glutamate, sodium pyruvate or medium-chain triglycerides (MCT), led to increased food intake and body weight gain near or back to that on chow diet. No such effect was observed when supplementing the diet with other sources of fat that contain long-chain fatty acids. Furthermore, when these supplements were added to a sucrose solution administered enterally to the mice, which has been shown previously to lead to elevated blood ammonia as well as altered hepatic metabolite levels in Ctrn/mGPP-KO mice, this led to metabolic correction. The elevated hepatic glycerol 3-phosphate and citrulline levels after sucrose administration were suppressed by the administration of sodium pyruvate, alanine, sodium glutamate and MCT, although the effect of MCT was relatively small. Low hepatic citrate and increased lysine levels were only found to be corrected by sodium pyruvate, while alanine and sodium glutamate both corrected hepatic glutamate and aspartate levels. Overall, these results suggest that dietary factors including increased protein content, supplementation of specific amino acids like alanine and sodium glutamate, as well as sodium pyruvate and MCT all show beneficial effects on citrin deficiency by increasing the carbohydrate tolerance of Ctrn/mGPD-KO mice, as observed through increased food intake and maintenance of body weight.
authors.affiliation: Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
authors.forename: Takeyori
authors.initials: T
authors.lastname: Saheki
authors.forename: Kanako
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ono
authors.forename: Natsumi
authors.initials: N
authors.lastname: Katsura
authors.forename: Mana
authors.initials: M
authors.lastname: Yokogawa
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yoshidumi
authors.forename: Sumie
authors.initials: S
authors.lastname: Furuie
authors.forename: Eishi
authors.initials: E
authors.lastname: Kuroda
authors.forename: Miharu
authors.initials: M
authors.lastname: Ushikai
authors.forename: Akihiro
authors.initials: A
authors.lastname: Asakawa
authors.forename: Akio
authors.initials: A
authors.lastname: Inui
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: David S
authors.initials: DS
authors.lastname: Sinasac
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Keiko
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000409:Alanine / Q000008:administration & dosage; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D002780:Cholestasis, Intrahepatic / Q000150:complications / Q000178:diet therapy* / Q000378:metabolism; D020159:Citrullinemia / Q000150:complications / Q000178:diet therapy* / Q000378:metabolism; D004044:Dietary Proteins / Q000008:administration & dosage; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects*; D005260:Female; D005526:Food, Formulated; D005993:Glycerolphosphate Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D019289:Pyruvic Acid / Q000008:administration & dosage; D012970:Sodium Glutamate / Q000008:administration & dosage; D013395:Sucrose / Q000008:administration & dosage; D014280:Triglycerides / Q000008:administration & dosage
chemical_list: D004044:Dietary Proteins; D033681:Mitochondrial Membrane Transport Proteins; C492277:Slc25a13 protein, mouse; D014280:Triglycerides; D013395:Sucrose; D019289:Pyruvic Acid; D005993:Glycerolphosphate Dehydrogenase; D000409:Alanine; D012970:Sodium Glutamate