FBP1 promotes ABCG2-mediated uric acid excretion through activation of the PI3K/AKT/CREB signaling pathway.

Hyperuricaemia, a metabolic disorder, is characterized by abnormally elevated serum uric acid (SUA) levels. Fructose-1,6-bisphosphatase (FBPase), a key rate-limiting enzyme in gluconeogenesis, catalyses the irreversible conversion of fructose-1,6-bisphosphate (F-1,6-BP) to fructose-6-phosphate (F-6-P). In humans, FBPase deficiency disorder (OMIM #229700) is an autosomal recessive inborn error of metabolism characterized by fasting-induced hypoglycaemia, life-threatening lactic acidosis, hyperuricaemia, and hepatosteatosis. However, the exact pathophysiological mechanisms driving hyperuricaemia remain unknown. To systematically investigate the regulatory role of FBPase in urate homeostasis, we developed in vitro models encompassing major metabolic tissues-HK-2 cells (kidney), LoVo/Caco-2 cells (intestinal epithelium) and HepG2 cells (liver). Our results demonstrate that FBP1 ablation markedly downregulates ABCG2 protein expression in renal (HK-2) and intestinal (LoVo/Caco-2) epithelial cells, thereby inducing a hyperuricaemic-prone metabolic state. Notably, in HepG2 cells, FBP1 deficiency unexpectedly led to reduced intracellular urate accumulation, indicating an inverse phenotype. Mechanistically, FBP1 sustained uric acid homeostasis through the orchestration of the PI3K/AKT/CREB signalling axis, driving functional ABCG2 expression. In summary, FBP1 plays a crucial role in uric acid metabolism, and its reduction leads to impaired uric acid excretion, consequently causing hyperuricaemia.