740 - Exploring the Therapeutic Potential of UX007 (Triheptanoin) in Citrin Deficiency Mouse Model

Publication Number: 740.4807

Eri Imagawa, The Jikei University School of Medicine, Tokyo, Tokyo, Japan; Kimihiko Oishi, The Jikei University School of Medicine, Tokyo, Tokyo, Japan

Background: Citrin deficiency (CD) is an inherited metabolic disorder that may present early in life with metabolic disturbances, including hypoglycemia, failure to thrive, fatigue, fatty liver, hyperammonemia, and distinctive dietary dislike for carbohydrate-rich diet. Nutritional interventions, such as medium-chain triglyceride (MCT) oil supplementation, have shown benefits for CD by replenishing citric acid cycle intermediates through anaplerotic effects. Triheptanoin, a triglyceride composed of three seven-carbon fatty acids, is metabolized via beta-oxidation to produce both acetyl-CoA and propionyl-CoA, the latter of which is converted to succinyl-CoA. CD is hypothesized to involve a deficiency in energy production due to insufficient anaplerosis, reflected by frequent hypoglycemia after infancy. Therefore, triheptanoin, with its enhanced capacity to restore citric acid cycle intermediates through succinyl-CoA production, may offer a more effective therapeutic approach than MCT oil.

Objective: To assess the efficacy of triheptanoin in improving CD-associated hepatic pathologies, such as fatty liver and hypoglycemia, using a Citrin-knockout (KO) mouse model.

Design/Methods: Citrin-KO and wild-type mice were fed a high-carbohydrate AIN-93M diet with or without triheptanoin (10% of total caloric intake) for one week. Blood samples were collected for biochemical analysis, and liver tissues were examined histologically and for hepatic triglyceride (TG) content. Computed tomography (CT) scans were performed on days -1, 3, and 7 to monitor fatty liver progression.

Results: Citrin-KO mice on the AIN-93M diet alone had lower average blood glucose levels than wild-type mice, indicating hypoglycemia. Triheptanoin treatment decreased glucose levels in wild-type mice but increased them in Citrin-KO mice. Histological analysis and CT scans revealed mild to severe lipid accumulation across all groups, regardless of triheptanoin administration. However, the average hepatic TG content in Citrin-KO mice on the AIN-93M diet alone was significantly higher than in wild-type mice (20.6 vs. 9.2 mg/g liver). Notably, triheptanoin treatment reduced hepatic TG levels in Citrin-KO mice to an average of 9.9 mg/g liver.

Conclusion(s): This study provides novel insights into the therapeutic potential of triheptanoin for CD. Our findings suggest that replacing dietary carbohydrates with triheptanoin may help prevent the development of fatty liver and hypoglycemia in CD. However, the variability in fat accumulation across samples likely reflects the phenotypic heterogeneity observed in human CD.