ABSTRACT
The citrin/mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) double-knockout mouse displays phenotypic attributes of both neonatal intrahepatic cholestasis and adult-onset type II citrullinemia, making it a suitable model of human citrin deficiency. In the present study, we investigated metabolic disturbances in the livers of wild-type, citrin (Ctrn) knockout, mGPD knockout, and Ctrn/mGPD double-knockout mice following oral sucrose versus saline administration using metabolomic approaches. By using gas chromatography/mass spectrometry and capillary electrophoresis/mass spectrometry, we found three general groupings of metabolite changes in the livers of the double-knockout mice following sucrose administration that were subsequently confirmed using liquid chromatography/mass spectrometry or enzymatic methods: a marked increase of hepatic glycerol 3-phosphate, a generalized decrease of hepatic tricarboxylic acid cycle intermediates, and alterations of hepatic amino acid levels related to the urea cycle or lysine catabolism including marked increases in citrulline and lysine. Furthermore, concurrent oral administration of sodium pyruvate with sucrose ameliorated the hyperammonemia induced by sucrose, as had been shown previously, as well as almost completely normalizing the hepatic metabolite perturbations found. Overall, we have identified additional metabolic disturbances in double-KO mice following oral sucrose administration, and provided further evidence for the therapeutic use of sodium pyruvate in our mouse model of citrin deficiency.
Subject(s)
Calcium-Binding Proteins/deficiency , Glycerolphosphate Dehydrogenase/genetics , Liver/metabolism , Metabolome , Mitochondria/metabolism , Organic Anion Transporters/deficiency , Ammonia/blood , Animals , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Citric Acid Cycle , Disease Models, Animal , Electrophoresis, Capillary , Gas Chromatography-Mass Spectrometry , Glycerolphosphate Dehydrogenase/metabolism , Glycolysis , Humans , Liver/drug effects , Metabolomics , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/enzymology , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Pyruvic Acid/pharmacology , Sucrose/administration & dosage , Urea/metabolismABSTRACT
In this paper, we describe the historical aspects of citrin and citrin deficiency, characteristic food preference and food aversion of citrin-deficient subjects, and carbohydrate toxicity in relation to ureogenesis and issues of the conventional treatment procedures for hyperammonemia in citrin deficiency, leading to current treatment concepts for citrin deficiency. We also emphasize the importance of a citrin deficiency mouse model in elucidating the pathophysiology and developing novel therapeutics based on the pathophysiology, such as sodium pyruvate.
