Secondary (iso)BAs Cooperate with Endogenous Ligands to Activate FXR Under Physiological and Pathological Conditions

Overview

Journal Biochim Biophys Acta Mol Basis Dis

Publisher Elsevier

Specialties Biochemistry
Biophysics
Genetics
Molecular Biology

Date 2021 Apr 25

PMID 33895309

Citations 4

Authors

Alex Zaufel

Sandra M W van de Wiel

Lu Yin

Gunter Fauler

Daphne Chien

Xinzhong Dong

John F Gilmer

Jennifer K Truong

Paul A Dawson

Stan F J van de Graaf

Peter Fickert

Tarek Moustafa

Affiliations

Soon will be listed here.

Abstract

Aim: Investigate the ability of BA-stereoisomers to bind and modulate FXR under physiological/pathological conditions.

Methods: Expression-profiling, luciferase-assays, fluorescence-based coactivator-association assays, administration of (iso)-BAs to WT and cholestatic mice.

Results: 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.

Conclusion: 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.

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