J. Lipid Res.
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A more recent version of this article appeared on December 1, 2007

Papers In Press, published online ahead of print September 6, 2007
J. Lipid Res., doi:10.1194/jlr.M700351-JLR200
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Submitted on August 6, 2007
Revised on September 6, 2007
Accepted on September 6, 2007

FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption

Diana Jung, Takeshi Inagaki, Paul A. Dawson, Steven A. Kliewer, David J. Mangelsdorf, and Antonio Moschetta

Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050

Corresponding Author: davo.mango{at}utsouthwestern.edu

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, 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 (SHP) to repress bile acid synthesis. Here, we show that the FXR-FGF15 pathway is disrupted in mice lacking apical ileal bile acid transporter (ASBT), a model of bile acid malabsorption. Treatment of Asbt–/– mice with either a synthetic FXR agonist or FGF15 down-regulates hepatic cholesterol 7a-hydroxylase (CYP7A1) 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.


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