Analysis of bile acid-induced regulation of FXR target genes in human liver slices.
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 7alpha hydroxylase, hepatocyte nuclear factor (HNF)1, HNF4 and organic anion transporting peptide (OATP)1B1. OATP1B3, FXR, HNF3beta 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.
Jung
Diana
D
Division of Pharmacology and Neurology, Biozentrum, University of Basel, Basel, Switzerland. Diana.Jung@unibas.ch
Elferink
Marieke G L
MG
Stellaard
Frans
F
Groothuis
Geny M M
GM
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D002352:Carrier Proteins; D002635:Chenodeoxycholic Acid; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D005765:Gastrointestinal Agents; D053583:Interleukin-1beta; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000099150:Receptor, Farnesoid X-Activated