Fibroblast Growth Factor (Fgf) 21 is a Novel Target Gene of Glucocorticoid Receptor

Abstract

Fibroblast growth factor (Fgf) 21 is a metabolic regulator that plays an important role in the maintenance of glucose, lipid, and energy homeostasis. Recent studies also suggest that Fgf21 induction can attenuate chemical‐induced toxicities, such as of acetaminophen, alcohol and dioxin. Glucocorticoid receptor (GR) is indispensable for cell growth and development, drug metabolism as well as immune response. However, the impact of GR activation on regulation of Fgf21 is unknown. The present study was designed to investigate whether activation of GR by the synthetic glucocorticoid Dexamethasone (DEX), can alter Fgf21 expression. Our results showed that in mouse liver, both low (2mg/kg) and high (50mg/kg) doses of DEX up‐regulated Fgf21 mRNA and protein expression. In addition, DEX induced Fgf21 mRNA and protein expression in both mouse (Hepa1c1c7) and human (Hep3B) hepatoma cells in a concentration‐ and time‐dependent manner. Generally, DEX produces its effects via activation of GR and/or pregnane X receptor (PXR). By using PXR‐null mouse model, we showed that 50mg/kg of DEX induced Fgf21 mRNA expression similarly in both wild‐type and PXR‐null mouse liver, indicating that the induction of Fgf21 by DEX is PXR‐independent. The in silico DNA sequence analysis revealed the presence of several putative GR response elements (GREs) in the 3kb promoter of mouse and human Fgf21/FGF21 genes. Further, GR silencing using GR‐specific siRNA, attenuated DEX‐induced Fgf21 expression in both mouse (Hepa1c1c7) and human (Hep3B) hepatoma cells. In summary, activation of GR induced Fgf21 expression in mouse liver as well as in cultured mouse and human hepatocytes.