RT Journal Article
T1 Interaction of glucocorticoids with FXR/FGF19/FGF21-mediated ileum-liver crosstalk.
A1 Al-Aqil, Faten A
A1 Monte, Maria J
A1 Peleteiro-Vigil, Ana
A1 Briz, Oscar
A1 Rosales, Ruben
A1 González, Raquel
A1 Aranda, Carlos J
A1 Ocón, Borja
A1 Uriarte, Iker
A1 de Medina, Fermín Sánchez
A1 Martinez-Augustín, Olga
A1 Avila, Matías A
A1 Marín, José J G
A1 Romero, Marta R
K1 Cholestasis
K1 Gene regulation
K1 Intestine
K1 Metabolism
K1 Transport
AB At 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.
SN 0925-4439
YR 2018
FD 2018-06-06
LK http://hdl.handle.net/10668/12564
UL http://hdl.handle.net/10668/12564
LA en
DS RISalud
RD Apr 10, 2025