Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury

Significance Bone is the main source of fibroblast growth factor 23 (FGF23), which is important for phosphate and vitamin D homeostasis. In acute kidney injury (AKI), high blood levels of FGF23 are positively correlated with disease progression and increased risk of mortality. Reducing adverse plasma FGF23 levels in AKI patients is favorable. We showed here that hepatocytes are the major source of circulating FGF23, and orphan nuclear receptor ERR-γ is a novel transcriptional regulator of hepatic FGF23 production in AKI. Liver-specific depletion of ERR-γ or ERR-γ inverse agonist, GSK5182, significantly reduced plasma levels of FGF23 in AKI. This study reveals liver is the source of FGF23 and a therapeutic strategy to control pathologically adverse plasma FGF23 levels in AKI.