Allosteric modulation of the farnesoid X receptor by a small molecule

Abstract The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dysl...

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Autores principales:	Matthias Gabler, Jan Kramer, Jurema Schmidt, Julius Pollinger, Julia Weber, Astrid Kaiser, Frank Löhr, Ewgenij Proschak, Manfred Schubert-Zsilavecz, Daniel Merk
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a1fdcd19a33746d6872e6c8a2493fca2
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spelling	oai:doaj.org-article:a1fdcd19a33746d6872e6c8a2493fca22021-12-02T11:40:24ZAllosteric modulation of the farnesoid X receptor by a small molecule10.1038/s41598-018-25158-52045-2322https://doaj.org/article/a1fdcd19a33746d6872e6c8a2493fca22018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25158-5https://doaj.org/toc/2045-2322Abstract The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.Matthias GablerJan KramerJurema SchmidtJulius PollingerJulia WeberAstrid KaiserFrank LöhrEwgenij ProschakManfred Schubert-ZsilaveczDaniel MerkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Matthias Gabler Jan Kramer Jurema Schmidt Julius Pollinger Julia Weber Astrid Kaiser Frank Löhr Ewgenij Proschak Manfred Schubert-Zsilavecz Daniel Merk Allosteric modulation of the farnesoid X receptor by a small molecule
description	Abstract The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
format	article
author	Matthias Gabler Jan Kramer Jurema Schmidt Julius Pollinger Julia Weber Astrid Kaiser Frank Löhr Ewgenij Proschak Manfred Schubert-Zsilavecz Daniel Merk
author_facet	Matthias Gabler Jan Kramer Jurema Schmidt Julius Pollinger Julia Weber Astrid Kaiser Frank Löhr Ewgenij Proschak Manfred Schubert-Zsilavecz Daniel Merk
author_sort	Matthias Gabler
title	Allosteric modulation of the farnesoid X receptor by a small molecule
title_short	Allosteric modulation of the farnesoid X receptor by a small molecule
title_full	Allosteric modulation of the farnesoid X receptor by a small molecule
title_fullStr	Allosteric modulation of the farnesoid X receptor by a small molecule
title_full_unstemmed	Allosteric modulation of the farnesoid X receptor by a small molecule
title_sort	allosteric modulation of the farnesoid x receptor by a small molecule
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/a1fdcd19a33746d6872e6c8a2493fca2
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Allosteric modulation of the farnesoid X receptor by a small molecule

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