Toxicity of sugars and identification of markers for pathophysiology in citrin deficiency leading to development of novel therapeutics

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We have established a model mouse of citrin deficiency causing neonatal intrahepatic cholestasis(NICCD) at neonatal period and adult-onset type II citrullinemia(CTLN2) at adult age. We showed that administration of sugars to the mice caused deterioration such as hyperammonemia. From the metabolomics analysis, we found that administration of sugars induced a marked increase in hepatic glycerol-3-phosphate(G3P), which is useful as a biomarker for citrin deficiency. We found that dietary change from high protein to low protein induced a decreased body weight, mimicking growth retardation or skinniness in the disease and that addition of substance such as protein, amino acids, pyruvate and medium-chain triglyceride to the low-protein diet increased food intake and body weight.