Al-Aqil, Faten AMonte, Maria JPeleteiro-Vigil, AnaBriz, OscarRosales, RubenGonzález, RaquelAranda, Carlos JOcón, BorjaUriarte, Ikerde Medina, Fermín SánchezMartinez-Augustín, OlgaAvila, Matías AMarín, José J GRomero, Marta R2023-01-252023-01-252018-06-060925-4439http://hdl.handle.net/10668/12564At high doses, glucocorticoids (GC) have been associated with enhanced serum bile acids and liver injury. We have evaluated the effect of GC, in the absence of hepatotoxicity, on FXR/FGF91(Fgf15)/FGF21-mediated ileum-liver crosstalk. Rats and mice (wild type and Fxr-/-, Fgf15-/- and int-Gr-/- strains; the latter with GC receptor (Gr) knockout selective for intestinal epithelial cells), were treated (i.p.) with dexamethasone, prednisolone or budesonide. In both species, high doses of GC caused hepatotoxicity. At a non-hepatotoxic dose, GC induced ileal Fgf15 down-regulation and liver Fgf21 up-regulation, without affecting Fxr expression. Fgf21 mRNA levels correlated with those of several genes involved in glucose and bile acid metabolism. Surprisingly, liver Cyp7a1 was not up-regulated. The expression of factors involved in transcriptional modulation by Fxr and Gr (p300, Drip205, CBP and Smrt) was not affected. Pxr target genes Cyp3a11 and Mrp2 were not up-regulated in liver or intestine. In contrast, the expression of some Pparα target genes in liver (Fgf21, Cyp4a14 and Vanin-1) and intestine (Vanin-1 and Cyp3a11) was altered. In mice with experimental colitis, liver Fgf21 was up-regulated (4.4-fold). HepG2 cells transfection with FGF21 inhibited CYP7A1 promoter (prCYP7A1-Luc2). This was mimicked by pure human FGF21 protein or culture in medium previously conditioned by cells over-expressing FGF21. This response was not abolished by deletion of a putative response element for phosphorylated FGF21 effectors present in prCYP7A1. In conclusion, GC interfere with FXR/FGF19-mediated intestinal control of CYP7A1 expression by the liver and stimulate hepatic secretion of FGF21, which inhibits CYP7A1 promoter through an autocrine mechanism.enCholestasisGene regulationIntestineMetabolismTransportAnimalsAutocrine CommunicationBile Acids and SaltsCholesterolCholesterol 7-alpha-HydroxylaseColitisDisease Models, AnimalFemaleFibroblast Growth FactorsGlucocorticoidsHep G2 CellsHumansIleumLiverMaleMiceMice, Inbred C57BLMice, KnockoutRatsRats, WistarReceptors, Cytoplasmic and NuclearSignal TransductionUp-Regulationresearch article29883717open access10.1016/j.bbadis.2018.06.003https://doi.org/10.1016/j.bbadis.2018.06.003