Regulation of Fgf15 expression in the intestine by glucocorticoid receptor

Abstract

Fibroblast growth factor 15 (FGF15) was previously identified to be highly expressed in the ileum and functions as an endocrine factor to regulate bile acid synthesis in the liver. FGF15 targets its receptor fibroblast growth factor receptor 4 in the liver and serves important roles in energy metabolism, including bile acid homeostasis, glucose metabolism and protein synthesis. The expression of FGF15 is known to be regulated by the transcription factor farnesoid X receptor (FXR). In the present study, reverse transcription-quantitative polymerase chain reaction was used for measuring Fgf15 expression from the animal and tissue culture experiments, and it was identified that dexamethasone, a drug widely used in anti-inflammation therapy, and a classical inducer of glucocorticoid receptor (GR)- and pregnane X receptor (PXR)-target genes, may downregulate Fgf15 expression in the ileum. GR was identified to be highly expressed in the ileum by western blot analysis. Furthermore, it was demonstrated that the downregulation of Fgf15 by dexamethasone is due to the repression of ileal FXR activity via GR; however, not PXR, in the ileum. The present results provide insight for a better understanding of the adverse effects associated with dexamethasone therapy.

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“…Bile acids are microbial-secreted metabolic regulators that bind to FXR to activate Nr0b2 (Shp1) blocking the synthesis of bile acids in the liver and uptake in the ileum [ 73 ]. Activated FXR is also responsible for enhanced secretion of Fgf15 (fibroblast growth factor 15) in ileum, that reduces bile acid formation in the liver via binding with Fgfr4 [ 74 ]. Therefore, we hypothesized that Au@P-NPs treatment may down-regulate Nr0b2 expression.…”

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“…This result suggests that Mediators of Inflammation the increased flora in the colon of mice with UC is also involved in BA metabolism. Jia et al [58] indicated that FGF15 plays an important role in energy metabolism, including BA homeostasis, glucose metabolism, and protein synthesis. FXR is a nuclear receptor expressed mainly in intestinal tissues that regulate BA, lipid, and glucose homeostasis [59].…”