2478-P: Uridine-Mediated Cross Talk of Hepatocytes and Adipocytes Drives Diet-Induced Obesity and MASLD

Introduction and Objective: Uridine is an uracil-conjugated nucleoside and plays an important role in maintaining normal metabolism. Fasting blood uridine levels are elevated in obesity and type 2 diabetes (T2D), but the significance of hepatic uridine biosynthesis in the etiology of both remains elusive. We found that de novo pyrimidine synthesis in the liver is reduced by fasting and by diet-induced obesity (DIO) in mice and in humans with MASLD. Consistently, both adipocytes and hepatocytes are capable of de novo pyrimidine synthesis, but only hepatocytes are found to be suppressed by a high-fat diet for pyrimidine synthesis. Methods: To explore the underlying mechanism, we generated a mouse model with hepatocyte-selective knockout of Cad, the first and rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. Results: We demonstrated that suppression of hepatic pyrimidine synthesis promotes DIO with fatty liver. Moreover, the Cad KO mice exhibited a striking elevation in gluconeogenesis and hepatic lipogenesis, phenotypically mimicking the selective insulin resistance observed in rodent models of type 2 diabetes. Remarkably, the elimination of uridine supply from hepatocytes in the Cad KO mice has no impact on circulating uridine levels, presumably due to an increase in uridine supply from adipocytes through a uridine-mediated crosstalk of the liver and fat. Conclusion: Our study suggests a new paradigm for the etiology of metabolic deterioration in DIO, in which perturbations in uridine homeostasis promote obesity and T2D, which might contribute to the pathogenesis of MASLD.