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Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.

Authors :
Ijssennagger, Noortje
Janssen, Aafke W.F.
Milona, Alexandra
Ramos Pittol, José M.
Hollman, Danielle A.A.
Mokry, Michal
Betzel, Bark
Berends, Frits J.
Janssen, Ignace M.
van Mil, Saskia W.C.
Kersten, Sander
Source :
Journal of Hepatology. May2016, Vol. 64 Issue 5, p1158-1166. 9p.
Publication Year :
2016

Abstract

Background & Aims The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), 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 alters hepatic expression of many genes. However, no data are available on the effects of OCA in the 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. Wild-type 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 six novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in high or low density lipoprotein observed in NASH and primary biliary cholangitis patients treated with OCA based on the genomic expression profile in hPCLS. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
01688278
Volume :
64
Issue :
5
Database :
Academic Search Index
Journal :
Journal of Hepatology
Publication Type :
Academic Journal
Accession number :
113951635
Full Text :
https://doi.org/10.1016/j.jhep.2016.01.016