Pentacyclic triterpenes modulate farnesoid X receptor expression in colonic epithelial cells: Implications for colonic secretory function.

Autor: Fallon CM; The School of Pharmacy and Biomolecular Sciences, RCSI, Beaumont Hospital, Dublin, Ireland. Electronic address: cfallon@rcsi.com., Smyth JS; The School of Pharmacy and Biomolecular Sciences, RCSI, Beaumont Hospital, Dublin, Ireland., Quach A; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA., Lajczak-McGinley N; The School of Pharmacy and Biomolecular Sciences, RCSI, Beaumont Hospital, Dublin, Ireland., O'Toole A; Department of Gastroenterology, Beaumont Hospital, Dublin, Ireland., Barrett KE; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA; Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, USA., Sheridan H; NatPro, Centre for Natural Product Research, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland., Keely SJ; The School of Pharmacy and Biomolecular Sciences, RCSI, Beaumont Hospital, Dublin, Ireland.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2022 Nov; Vol. 298 (11), pp. 102569. Date of Electronic Publication: 2022 Oct 06.
DOI: 10.1016/j.jbc.2022.102569
Abstrakt: The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important regulator of intestinal and metabolic function. Previous studies suggest that pentacyclic triterpenes (PCTs), a class of plant-derived bioactive phytochemical, can modulate FXR activity and may therefore offer therapeutic benefits. Here, we investigated the effects of a prototypical PCT, hederagenin (HG), on FXR expression, activity, and antisecretory actions in colonic epithelial cells. T 84 cells and murine enteroid-derived monolayers were employed to assess HG effects on FXR expression and activity in colonic epithelia. We measured mRNA levels by qRT-PCR and protein by ELISA and immunoblotting. Transepithelial Cl - secretion was assessed as changes in short circuit current in Ussing chambers. We determined HG treatment (5-10 μM) alone did not induce FXR activation but significantly increased expression of the receptor, both in T 84  cells and murine enteroid-derived monolayers. This effect was accompanied by enhanced FXR activity, as assessed by FGF-15/19 induction in response to the synthetic, GW4064, or natural FXR agonist, chenodeoxycholic acid. Effects of HG on FXR expression and activity were mimicked by another PCT, oleanolic acid. Furthermore, we found FXR-induced downregulation of cystic fibrosis transmembrane conductance regulator Cl - channels and inhibition of transepithelial Cl - secretion were enhanced in HG-treated cells. These data demonstrate that dietary PCTs have the capacity to modulate FXR expression, activity, and antisecretory actions in colonic epithelial cells. Based on these data, we propose that plants rich in PCTs, or extracts thereof, have excellent potential for development as a new class of "FXR-targeted nutraceuticals".
Competing Interests: Conflict of interest The authors have no conflicts of interest to disclose.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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