Analysis of bile acid-induced regulation of FXR target genes in human liver slices

Authors

  • Diana Jung,

    1. Division of Pharmacology and Neurology, Biozentrum, University of Basel, Basel, Switzerland
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    • *Authors contributed equally to this study.

  • Marieke G. L. Elferink,

    1. Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands
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    • *Authors contributed equally to this study.

  • Frans Stellaard,

    1. Laboratory Pediatrics, Center for Liver, Digestive and Metabolic Diseases, UMCG, Groningen, The Netherlands
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  • Geny M. M. Groothuis

    1. Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands
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Correspondence
Diana Jung, Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH – 4056 Basel, The Netherlands.
Tel: +0041- 612-672-241
Fax: +0041- 612-672-208
e-mail: Diana.Jung@unibas.ch

Abstract

Information about the role of nuclear receptors has rapidly increased over the last decade. However, details about their role in human are lacking. Owing to species differences, a powerful human in vitro system is needed. This study uses for the first time precision-cut human liver slices in the nuclear receptor field. The farnesoid X receptor (FXR) was chosen as a model. We were able to demonstrate that human liver slices efficiently take up bile acids and show a stable expression of a wide variety of genes relevant for bile acid metabolism, including bile acid transporters, cytochrome P450 enzymes and transcription factors. Treatment with chenodeoxycholate induced small heterodimer partner, bile salt export pump and p-glycoprotein, ABCB4 and repressed cholesterol 7α hydroxylase, hepatocyte nuclear factor (HNF)1, HNF4 and organic anion transporting peptide (OATP)1B1. OATP1B3, FXR, HNF3β and cytochrome P450 enzyme remained relatively constant. In contrast to what has been observed in mice and rat studies, SHP induction did not result in repression of sodium-dependent bile acid cotransporter expression. Further, regulation of genes seemed to be dependent on concentration and time. Taken together, the study shows that the use of liver slices is a powerful technique that enables to study nuclear receptors in the human liver.

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