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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 11 / metabolism
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Allosteric Regulation
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Bile Acids and Salts / metabolism
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Gene Expression Regulation
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HEK293 Cells
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HeLa Cells
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Hep G2 Cells
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Humans
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Imatinib Mesylate / analogs & derivatives
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Imatinib Mesylate / chemistry
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Imatinib Mesylate / pharmacology*
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / chemistry
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Transcription Factors* / analysis
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Transcription Factors* / metabolism
Substances
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ABCB11 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 11
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Bile Acids and Salts
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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nuclear receptor subfamily 0, group B, member 2
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farnesoid X-activated receptor
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Imatinib Mesylate