Chenodeoxycholic acid regulates fibroblast growth factor 23 gene expression via estrogen-related receptor γ in human hepatoma Huh7 cells

Abstract

Fibroblast growth factor 23 (FGF23) is a glycoprotein that belongs to the FGF19 subfamily and participates in phosphate and vitamin D homeostasis. Chenodeoxycholic acid (CDCA), one of the primary bile acids, is reported to induce the secretion of FGF19 subfamily members, FGF21 and FGF19, in hepatocytes. However, whether and how CDCA influences FGF23 gene expression are largely unknown. Thus, we performed real-time polymerase chain reaction and Western blot analyses to determine the mRNA and protein expression levels of FGF23 in Huh7 cells. CDCA upregulated estrogen-related receptor γ (ERRγ) alongside FGF23 mRNA and protein levels, while, the knockdown of ERRγ ablated the induction effect of CDCA on FGF23 expression. Promoter studies showed that CDCA-induced FGF23 promoter activity occurred partly through ERRγ binding directly to the ERR response element (ERRE) in the human FGF23 gene promoter. Finally, the inverse agonist of ERRγ, GSK5182 inhibited the induction of FGF23 by CDCA. Overall, our results revealed the mechanism of CDCA-mediated FGF23 gene upregulation in the human hepatoma cell line. Moreover, the ability of GSK5182 to reduce CDCA-induced FGF23 gene expression might represent a therapeutic strategy to control abnormal FGF23 induction in conditions that involve elevated levels of bile acids, such as nonalcoholic fatty liver disease and biliary atresia.