Dr. Araceli del Arco and Dr. Laura Contreras
Universidad Autónoma de Madrid, Spain
Metabolic Changes and Disease Progression in Citrin Deficiency
This project aims to elucidate the pathophysiology of Citrin Deficiency (CD), a rare metabolic liver disorder caused by CITRIN/SLC25A13 mutations, using a newly developed double-knockout (DLKO) mouse model lacking both aspartate-glutamate mitochondrial carriers in liver. By combining global citrin deletion with liver-specific aralar knockout , mimicking the human hepatic profile, this model reproduces key metabolic features of CD enabling investigation of disease mechanisms and progression across developmental stages.
The project addresses four major objectives: (1) to study the temporal progression of CD from neonatal intrahepatic cholestasis (NICCD) to the adolescent/adult form (AACD), using metabolic stressors like acetaminophen and alcohol to identify biomarkers and mechanisms underlying disease progression; (2) to investigate nutrient utilization in CD through amino acid and lipid metabolism studies in DLKO hepatocytes, complemented by systemic analyses using metabolic cages; (3) to evaluate the therapeutic potential of aralar re-expression for restoring metabolic functions, including gluconeogenesis, ureagenesis, and calcium-dependent regulation; and (4) to investigate the origin of elevated plasma arginine levels, exploring a possible renal contribution. We expect this research will identify biomarkers of disease progression, help defining compensatory mechanisms, and serve to evaluate novel therapeutic strategies.
(Updated October 2025)
