Farnesoid X receptor prevents hyperuricemia via activating ATP‐binding cassette subfamily G member 2

Abstract Background The farnesoid X receptor (FXR) is a nuclear receptor that regulates bile acid, lipid, and glucose metabolism. Its role in uric acid (UA) homeostasis, however, remains unclear. This study investigated the potential involvement of FXR in hyperuricemia and explored the underlying mechanisms. Methods FXR knockout mice ( n = 22) along with their littermate wild‐type controls ( n = 19) were used to assess serum UA concentrations and intestinal expression of ATP‐binding cassette subfamily G member 2 (ABCG2). Serum UA was quantified using a phosphotungstic acid assay. A hyperuricemia model was induced in C57BL/6 mice by yeast polysaccharide supplementation and potassium oxonate injection, followed by treatment with obeticholic acid (OCA), a selective FXR agonist. FXR and ABCG2 expression was evaluated by real‐time polymerase chain reaction, Western blot, and immunohistochemistry. In vitro, CT‐26 cells were exposed to high UA with or without OCA, and FXR expression was silenced using siRNA. The binding of FXR to the ABCG2 promoter was tested by dual‐luciferase reporter assay. Human intestinal tissues from patients with hyperuricemia (6 male/1 female) and healthy controls (5 male/1 female) were also analyzed. Results FXR knockout mice exhibited significantly higher serum UA levels than wild‐type controls (550.9 ± 106.3 vs. 336.3 ± 52.1 μmol/L, p < 0.001), accompanied by reduced intestinal ABCG2 expression. In hyperuricemic mice, OCA administration lowered serum UA concentrations and restored ABCG2 expression. In CT‐26 cells, OCA enhanced FXR and ABCG2 expression under high UA conditions (500 µmol/L), an effect blocked by FXR knockdown. Reporter assays demonstrated that FXR can activate the ABCG2 promoter. In human samples, intestinal FXR and ABCG2 expression were both significantly reduced in patients with hyperuricemia compared with controls ( p < 0.05). Conclusions FXR appears to exert anti‐hyperuricemic effects, at least in part, by upregulating intestinal ABCG2 expression. These findings highlight FXR as a potential therapeutic target in hyperuricemia and support further evaluation of FXR agonists in clinical settings.