Allosteric modulation of the farnesoid X receptor by a small molecule

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....

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Autores principales: Gabler, Matthias, Kramer, Jan, Schmidt, Jurema, Pollinger, Julius, Weber, Julia, Kaiser, Astrid, Löhr, Frank, Proschak, Ewgenij, Schubert-Zsilavecz, Manfred, Merk, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931576/
https://www.ncbi.nlm.nih.gov/pubmed/29717168
http://dx.doi.org/10.1038/s41598-018-25158-5
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author Gabler, Matthias
Kramer, Jan
Schmidt, Jurema
Pollinger, Julius
Weber, Julia
Kaiser, Astrid
Löhr, Frank
Proschak, Ewgenij
Schubert-Zsilavecz, Manfred
Merk, Daniel
author_facet Gabler, Matthias
Kramer, Jan
Schmidt, Jurema
Pollinger, Julius
Weber, Julia
Kaiser, Astrid
Löhr, Frank
Proschak, Ewgenij
Schubert-Zsilavecz, Manfred
Merk, Daniel
author_sort Gabler, Matthias
collection PubMed
description 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.
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spelling pubmed-59315762018-08-29 Allosteric modulation of the farnesoid X receptor by a small molecule Gabler, Matthias Kramer, Jan Schmidt, Jurema Pollinger, Julius Weber, Julia Kaiser, Astrid Löhr, Frank Proschak, Ewgenij Schubert-Zsilavecz, Manfred Merk, Daniel Sci Rep Article 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. Nature Publishing Group UK 2018-05-01 /pmc/articles/PMC5931576/ /pubmed/29717168 http://dx.doi.org/10.1038/s41598-018-25158-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gabler, Matthias
Kramer, Jan
Schmidt, Jurema
Pollinger, Julius
Weber, Julia
Kaiser, Astrid
Löhr, Frank
Proschak, Ewgenij
Schubert-Zsilavecz, Manfred
Merk, Daniel
Allosteric modulation of the farnesoid X receptor by a small molecule
title 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_short Allosteric modulation of the farnesoid X receptor by a small molecule
title_sort allosteric modulation of the farnesoid x receptor by a small molecule
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931576/
https://www.ncbi.nlm.nih.gov/pubmed/29717168
http://dx.doi.org/10.1038/s41598-018-25158-5
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