Secondary (iso)BAs cooperate with endogenous ligands to activate FXR under physiological and pathological conditions.
Animals
Bile Acids and Salts
/ pharmacology
Caco-2 Cells
Cell Line
Cell Line, Tumor
Cholestasis
/ drug therapy
Disease Models, Animal
Fibroblast Growth Factors
/ metabolism
HEK293 Cells
Hep G2 Cells
Humans
Ileum
/ drug effects
Isoxazoles
/ pharmacology
Ligands
Liver
/ drug effects
Male
Mice
RNA, Messenger
/ metabolism
Receptors, Cytoplasmic and Nuclear
/ metabolism
Signal Transduction
/ drug effects
Transcription Factors
/ metabolism
Bile acids
Enterohepatic, cholestasis, gene expression
Metabolism
Nuclear receptors
Journal
Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730
Informations de publication
Date de publication:
01 08 2021
01 08 2021
Historique:
received:
28
01
2021
revised:
24
03
2021
accepted:
19
04
2021
pubmed:
26
4
2021
medline:
18
11
2021
entrez:
25
4
2021
Statut:
ppublish
Résumé
IsoBAs, stereoisomers of primary and secondary BAs, are found in feces and plasma of human individuals. BA signaling via the nuclear receptor FXR is crucial for regulation of hepatic and intestinal physiology/pathophysiology. Investigate the ability of BA-stereoisomers to bind and modulate FXR under physiological/pathological conditions. Expression-profiling, luciferase-assays, fluorescence-based coactivator-association assays, administration of (iso)-BAs to WT and cholestatic mice. Compared to CDCA/isoCDCA, administration of DCA/isoDCA, UDCA/isoUDCA only slightly increased mRNA expression of FXR target genes; the induction was more evident looking at pre-mRNAs. Notably, almost 50% of isoBAs were metabolized to 3-oxo-BAs within 4 h in cell-based assays, making it difficult to study their actions. FRET-based real-time monitoring of FXR activity revealed that isoCDCA>CDCA stimulated FXR, and isoDCA and isoUDCA allowed fully activated FXR to be re-stimulated by a second dose of GW4064. In vivo co-administration of a single dose of isoBAs followed by GW4064 cooperatively activated FXR, as did feeding of UDCA in a background of endogenous FXR ligands. However, in animals with biliary obstruction and concomitant loss of intestinal BAs, UDCA was unable to increase intestinal Fgf15. In contrast, mice with an impaired enterohepatic circulation of BAs (Asbt-/-, Ostα-/-), administration of UDCA was still able to induce ileal Fgf15 and repress hepatic BA-synthesis, arguing that UDCA is only effective in the presence of endogenous FXR ligands. Secondary (iso)BAs cooperatively activate FXR in the presence of endogenous BAs, which is important to consider in diseases linked to disturbances in BA enterohepatic cycling.
Identifiants
pubmed: 33895309
pii: S0925-4439(21)00086-7
doi: 10.1016/j.bbadis.2021.166153
pmc: PMC8177068
mid: NIHMS1706919
pii:
doi:
Substances chimiques
Bile Acids and Salts
0
Isoxazoles
0
Ligands
0
RNA, Messenger
0
Receptors, Cytoplasmic and Nuclear
0
Transcription Factors
0
Fibroblast Growth Factors
62031-54-3
GW 4064
SR225WUZ0H
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
166153Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK047987
Pays : United States
Organisme : NIDDK NIH HHS
ID : R29 DK047987
Pays : United States
Organisme : Austrian Science Fund FWF
ID : W 1226
Pays : Austria
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.
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