title: Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
authors.forename: Noortje
authors.initials: N
authors.lastname: Ijssennagger
authors.affiliation: Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, 6703 HD Wageningen, The Netherlands.
authors.forename: Aafke W F
authors.initials: AWF
authors.lastname: Janssen
authors.affiliation: Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Milona
authors.affiliation: Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
authors.forename: José M
authors.initials: JM
authors.lastname: Ramos Pittol
authors.affiliation: Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
authors.forename: Danielle A A
authors.initials: DAA
authors.lastname: Hollman
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Department of Surgery, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands.
authors.forename: Bark
authors.initials: B
authors.lastname: Betzel
authors.affiliation: Department of Surgery, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands.
authors.forename: Frits J
authors.initials: FJ
authors.lastname: Berends
authors.affiliation: Department of Surgery, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands.
authors.forename: Ignace M
authors.initials: IM
authors.lastname: Janssen
authors.affiliation: Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands. Electronic address: S.W.C.vanmil@umcutrecht.nl.
authors.forename: Saskia W C
authors.initials: SWC
authors.lastname: van Mil
authors.affiliation: Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, 6703 HD Wageningen, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
mesh_terms: D000818:Animals; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D004247:DNA; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid
keywords: Farnesoid X receptor; Gene expression profiling; Human liver slices; Obeticholic acid