Allantoin promotes MASLD progression

Uric acid has garnered increasing attention for its association with metabolic dysfunction-associated steatotic liver disease (MASLD) in recent cross-sectional studies, although detailed understanding of its involvement remains limited. This study confirms a strong association between urate levels and elevated risk of both MASLD and type 2 diabetes (T2D) through a large-scale observational analysis of UK Biobank data. However, Mendelian randomization (MR) analysis involving over 2 million samples identified only causal effects of urate on serum triglyceride levels and the risk of T2D. Additionally, a targeted metabolomics study involving elderly Chinese participants revealed that, rather than UA, allantoin—a byproduct of UA oxidation—was significantly elevated in individuals with dyslipidemia or T2D. Notably, a significant negative correlation was found between serum allantoin level and fasting glucose, as well as serum triglyceride and cholesterol levels. Animal studies demonstrated that allantoin exacerbates hepatic lipid accumulation and glucose intolerance in mice fed a high-fat diet, which was accompanied by increased hepatic lipid biogenesis and reduced bile acid production. Interestingly, our findings indicate that allantoin exhibits a strong binding affinity for PPARa, suggesting that it may act as an inhibitor of PPARa, thereby promoting the progression of MASLD. These results underscore the critical role of allantoin, rather than UA, in the development of MASLD, offering valuable insights for the prediction and management of hepatic metabolic disorders. Overall design: For allantoin intervention, mice were fed on HFD for 4 weeks, the HFD-fed mice were then supplemented with allantoin in their drinking water at the concentrations of 0.06 mg/mL and 0.3mg/mL for additional 4 weeks. Liver were collected for RNA-seq.