Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disease associated with obesity and diabetes. Disruption of uridine homeostasis has been linked to both obesity and the onset of MASLD. However, the role of uridine in regulation of lipid metabolism remains poorly understood. Our project goal is to elucidate how uridine influences fatty acid metabolism during obesity and MASLD development. 

Methods: Bioinformatics analyses of omics data was performed with AI-based platform Yotta (DeepSpace Biology). Male C57BL/6 mice fed a chow or obesogenic high fat, fructose, cholesterol (FFC) diet for 8 weeks, received uridine (50 mg/kg) or vehicle for 3 weeks. Metabolic phenotype, liver injury, and tissue homeostasis were analyzed by multi-omics analysis, histological and molecular assays.  

Results: Unbiased bioinformatics analysis of spaceflight liver metabolomics data revealed a significant enrichment of fatty acids (p<0.03) and depletion of uridine (LogFC=-0.85, p<0.02) in flight vs. ground control mice. Concomitantly, liver expression of uridine 5’-monophosphate synthase (UMPS) was significantly downregulated in flight mice. UMPS was downregulated in human MASLD compared to normal livers (p<0.002). Targeted metabolomics analysis confirmed a significant time-dependent decrease of liver uridine in diet-induced MASLD mice. In vivo, uridine-treated FFC mice exhibited increased metabolic activity without changes in food and water intake, as compared to vehicle-treated FFC mice. In FFC mice, uridine reduced body, liver, and adipose tissue weight, protected from liver and muscle steatosis, and reduced intestinal inflammation, as confirmed by histological assessment. Liver phosphoproteomics analysis identified differential phosphorylation of proteins associated with mitochondrial fatty acid metabolism in FFC mice.  

Conclusions: Our findings indicate that UMPS downregulation and uridine depletion occur early in MASLD/obesity development and impair fatty acid oxidation, leading to lipid build-up over time. Further elucidation of uridine metabolism may uncover potential novel targets for obesity/MASLD treatment.