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: Takeyori Saheki, Kanako Inoue, Hiromi Ono, Natsumi Katsura, Mana Yokogawa, Yukari Yoshidumi, Sumie Furuie, Eishi Kuroda, Miharu Ushikai, Akihiro Asakawa, Akio Inui, Kazuhiro Eto, Takashi Kadowaki, David S Sinasac, Ken-Ichi Yamamura, Keiko Kobayashi
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 107 Issue 3 Pg. 322-9 (Nov 2012) ISSN: 1096-7206 [Electronic] United States
• PMID: 22921887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Dietary Proteins
• Mitochondrial Membrane Transport Proteins
• Slc25a13 protein, mouse
• Triglycerides
• Sucrose
• Pyruvic Acid
• Glycerolphosphate Dehydrogenase
• Alanine
• Sodium Glutamate

Topics

• Alanine (administration & dosage)
• Animals
• Body Weight (drug effects)
• Cholestasis, Intrahepatic (complications, diet therapy, metabolism)
• Citrullinemia (complications, diet therapy, metabolism)
• Dietary Proteins (administration & dosage)
• Disease Models, Animal
• Eating (drug effects)
• Female
• Food, Formulated
• Glycerolphosphate Dehydrogenase (deficiency, genetics)
• Humans
• Liver (drug effects, metabolism)
• Mice
• Mice, Knockout
• Mitochondria (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (deficiency, genetics)
• Pyruvic Acid (administration & dosage)
• Sodium Glutamate (administration & dosage)
• Sucrose (administration & dosage)
• Triglycerides (administration & dosage)