FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption.
Bile acid malabsorption, which in patients leads to excessive fecal bile acid excretion and diarrhea, is characterized by a vicious cycle in which the feedback regulation of bile acid synthesis is interrupted, resulting in additional bile acid production. Feedback regulation of bile acid synthesis is under the control of an endocrine pathway wherein activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), induces enteric expression of the hormone, fibroblast growth factor 15 (FGF15). In liver, FGF15 acts together with FXR-mediated expression of small heterodimer partner to repress bile acid synthesis. Here, we show that the FXR-FGF15 pathway is disrupted in mice lacking apical ileal bile acid transporter, a model of bile acid malabsorption. Treatment of Asbt-/- mice with either a synthetic FXR agonist or FGF15 downregulates hepatic cholesterol 7alpha-hydroxylase mRNA levels, decreases bile acid pool size, and reduces fecal bile acid excretion. These findings suggest that FXR agonists or FGF15 could be used therapeutically to interrupt the cycle of excessive bile acid production in patients with bile acid malabsorption.
Jung
Diana
D
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
Inagaki
Takeshi
T
Gerard
Robert D
RD
Dawson
Paul A
PA
Kliewer
Steven A
SA
Mangelsdorf
David J
DJ
Moschetta
Antonio
A
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists*; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D007555:Isoxazoles / Q000627:therapeutic use*; D008099:Liver; D008286:Malabsorption Syndromes / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists*; D000099150:Receptor, Farnesoid X-Activated