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Series GSE76162 Query DataSets for GSE76162
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
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.
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.
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
Organization name Wageningen University
Department Div. Human Nutrition & Health
Lab Nutrition, Metabolism & Genomics Group
Street address HELIX, Stippeneng 4
City Wageningen
ZIP/Postal code NL-6708WE
Country Netherlands
Platforms (1)
GPL11533 [MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version]
Samples (24)
GSM1975484 Liver_mouse_WT_INT747_rep1
GSM1975485 Liver_mouse_WT_vehicle_rep1
GSM1975486 Liver_mouse_FXRKO_vehicle_rep1
This SubSeries is part of SuperSeries:
GSE76163 Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid
BioProject PRJNA306504

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE76162_RAW.tar 105.7 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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