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Series GSE76161 Query DataSets for GSE76161
Status Public on Jan 27, 2016
Title Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [human]
Organism Homo sapiens
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 Precision-cut liver slices, prepared from liver biopsies obtained from obese subjects undergoing bariatric surgery, were incubated with the FXRα agonist obeticholic acid (OCA, INT-747, 6α-ethyl-chenodeoxycholic acid) or vehicle for 24hrs, after which gene expression was profiled by array.
Contributor(s) Ijssennagger N, Janssen AW, van Mil S, Kersten S
Citation(s) 26812075
Submission date Dec 18, 2015
Last update date Nov 08, 2016
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)
GPL11532 [HuGene-1_1-st] Affymetrix Human Gene 1.1 ST Array [transcript (gene) version]
Samples (6)
GSM1975478 PCLS_subject 3_DMSO_rep1
GSM1975479 PCLS_subject 3_INT747_rep1
GSM1975480 PCLS_subject 4_DMSO_rep2
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 PRJNA306505

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
GSE76161_RAW.tar 26.3 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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