Roles of an endogenous peptide ELABELA in ameliorating hyperuricemia by inhibiting uric acid production via CYP27A1-modulated bile acid metabolism in mice

ELABELA (ELA), an endogenous peptide, exhibits antioxidant and anti-inflammatory properties in the heart and kidney. This study aimed to explore the therapeutic potential of ELA in hyperuricemia (HUA) and its underlying mechanism. Male C57BL/6 mice were used to induce HUA via oral administration of adenine and potassium oxonate for 14 days. 32 or 11 amino-acid ELA peptides (ELA32 or ELA11) were intraperitoneally injected into HUA mice. Compared with the HUA group, both ELA peptides significantly reduced serum UA levels, as well as hepatic expression and activity of XOD. ELA32 also decreased BUN, serum creatinine, AST, ALT and Cholesterol levels while ELA11 diminished BUN and serum creatinine. Furthermore, both ELA peptides modulated bile acid (BA) synthesis, primarily through suppression of CYP27A1. Hepatic BA profiling revealed that HUA increased levels of taurochenodeoxycholic acid (TCDCA), whereas ELA treatment elevated levels of taurocholic acid (TCA), tauroursodeoxycholic acid (TUDCA), and tauro-β-muricholic acid (T-βMCA). ELA32 additionally promoted accumulation of cholic acid (CA) and taurodeoxycholic acid (TDCA). In human hepatocytes HepG2, both ELA peptides reduced H₂O₂-induced protein levels of XOD and CYP27A1, while enhanced FXR expression. CYP27A1 deficiency mimicked the effects of ELA32 on XOD and FXR expression under H₂O₂ stimulation. Moreover, TCA, TUDCA, TCDCA, CA and TDCA reversed H₂O₂-mediated regulation of XOD and FXR expression. These findings suggest that both ELA32 and ELA11 alleviate HUA in mice primarily by inhibiting XOD expression through CYP27A1-regulated BA metabolism. Our study suggests that ELA has therapeutic potential for the treatment of HUA.

Bile acid synthesis; CYP27A1; ELABELA; Hyperuricemia; Xanthine oxidase.