title: In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue.
abstract: We generated and characterized a firefly luciferase reporter mouse for the nuclear receptor farnesoid X receptor (FXR). This FXR reporter mouse has basal luciferase expression in the terminal ileum, an organ with well-characterized FXRalpha signaling. In vivo luciferase activity reflected the diurnal activity pattern of the mouse, and is regulated by both natural (bile acids, chenodeoxycholic acid) and synthetic (GW4064) FXRalpha ligands. Moreover, in vivo and in vitro analysis showed luciferase activity after GW4064 administration in the liver, kidney, and adrenal gland, indicating that FXRalpha signaling is functional in these tissues. Hepatic luciferase activity was robustly induced in cholestatic mice, showing that FXRalpha signaling pathways are activated in this disease. In conclusion, we have developed an FXR reporter mouse that is useful to monitor FXRalpha signaling in vivo in health and disease. The use of this animal could facilitate the development of new therapeutic compounds that target FXRalpha in a tissue-specific manner.
authors.affiliation: Institut de Génétique et Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Illkirch, France.
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: David H
authors.initials: DH
authors.lastname: Volle
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000311:Adrenal Glands / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D017930:Genes, Reporter / Q000187:drug effects; D007082:Ileum / Q000737:chemistry / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D008024:Ligands; D008156:Luciferases; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064