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In Vivo Imaging of Farnesoid X Receptor Activity Reveals the Ileum as the Primary Bile Acid Signaling Tissue

Institut de Génétique et Biologie Moléculaire et Cellulaire (S.M.H., D.H.V., J.A.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, and Institut Clinique de la Souris (J.A.), 67404 Illkirch, France; Howard Hughes Medical Institute and Department of Pharmacology (C.L.C., D.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Hôpitaux Universitaires de Strasbourg, Laboratoire de Biochimie Générale et Spécialisée (J.A.), 67000 Strasbourg, France

Address all correspondence and requests for reprints to: Johan Auwerx, Institut de Génétique et Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, Parc d’Innovation, 67404 Illkirch, France. E-mail: auwerx{at}igbmc.u-strasbg.fr.

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 FXR 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) FXR ligands. Moreover, in vivo and in vitro analysis showed luciferase activity after GW4064 administration in the liver, kidney, and adrenal gland, indicating that FXR signaling is functional in these tissues. Hepatic luciferase activity was robustly induced in cholestatic mice, showing that FXR signaling pathways are activated in this disease. In conclusion, we have developed an FXR reporter mouse that is useful to monitor FXR signaling in vivo in health and disease. The use of this animal could facilitate the development of new therapeutic compounds that target FXR in a tissue-specific manner.

NURSA Molecule Pages Link:

Nuclear Receptors:   FXRα

Ligands:   GW4064

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