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| Status |
Public on Jan 27, 2016 |
| Title |
Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [mouse] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA.
Methods: hPCLS were incubated with OCA for 24 h. WT or FXR -/- mice received OCA or vehicle by oral gavage for 7 days.
Results: Transcriptomic analysis showed that well-known FXR target genes, including NR0B2 (SHP), ABCB11 (BSEP), SLC51A (OSTα) and SLC51B (OSTβ) and ABCB4 (MDR3), are regulated by OCA in hPCLS. Ingenuity pathway analysis confirmed that 'FXR/RXR activation' is the most significantly changed pathway upon OCA treatment. Comparison of gene expression profiles in hPCLS and mouse livers identified 18 common potential FXR targets. ChIP-sequencing in mouse liver confirmed FXR binding to IR1 sequences of Akap13, Cgnl1, Dyrk3, Pdia5, PPP1R3B and Tbx6.
Conclusions: Our study shows that hPCLS respond to OCA treatment by upregulating well-known FXR target genes, demonstrating its suitability to study FXR-mediated gene regulation. We identified 6 novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in HDL/LDL observed in NASH and primary biliary cirrhosis patients treated with OCA based on the genomic expression profile in hPCLS.
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| Overall design |
Wild-type and FXR-/- mice received either a treatment with OCA (10 mg/kg/day) to pharmacologically activate FXR, or vehicle (1% methyl cellulose) daily by oral gavage for 7 days. Hereafter, mice were sacrificed and livers subjected to gene expression profiling.
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| Contributor(s) |
Ijssennagger N, Janssen AW, Kersten S, van Mil S |
| Citation(s) |
26812075 |
| Submission date |
Dec 18, 2015 |
| Last update date |
Apr 18, 2017 |
| Contact name |
Guido Hooiveld |
| E-mail(s) |
guido.hooiveld@wur.nl
|
| Organization name |
Wageningen University
|
| Department |
Div. Human Nutrition & Health
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| Lab |
Nutrition, Metabolism & Genomics Group
|
| Street address |
HELIX, Stippeneng 4
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| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
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| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (24)
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| This SubSeries is part of SuperSeries: |
| GSE76163 |
Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid |
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| Relations |
| BioProject |
PRJNA306504 |
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