TY - JOUR
T1 - Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid
AU - Ijssennagger, Noortje
AU - Janssen, Aafke W F
AU - Milona, Alexandra
AU - Ramos Pittol, José M
AU - Hollman, Danielle A A
AU - Mokry, Michal
AU - Betzel, Bark
AU - Berends, Frits J
AU - Janssen, Ignace M
AU - van Mil, Saskia W C
AU - Kersten, Sander
N1 - Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2016
Y1 - 2016
N2 - 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 24h. Wild-type or FXR(-/-) mice received OCA or vehicle by oral gavage for 7days.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.
AB - 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 24h. Wild-type or FXR(-/-) mice received OCA or vehicle by oral gavage for 7days.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.
KW - Farnesoid X receptor
KW - Obeticholic acid
KW - Human liver slices
KW - Gene expression profiling
U2 - 10.1016/j.jhep.2016.01.016
DO - 10.1016/j.jhep.2016.01.016
M3 - Article
C2 - 26812075
SN - 0168-8278
VL - 64
SP - 1158
EP - 1166
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 5
ER -