J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700351-JLR200 on September 6, 2007

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Journal of Lipid Research, Vol. 48, 2693-2700, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

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

Diana Jung*, Takeshi Inagaki*,{dagger}, Robert D. Gerard{dagger},§, Paul A. Dawson**, Steven A. Kliewer*,{dagger}, David J. Mangelsdorf1,* and Antonio Moschetta1,*,{dagger}{dagger},§§

* Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050
{dagger} Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050
§ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050
** Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157
{dagger}{dagger} Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Italy
§§ Clinica Medica A. Murri, University of Bari, 70124 Bari, Italy

Published, JLR Papers in Press, September 6, 2007.

1 To whom correspondence should be addressed. e-mail: davo.mango{at}utsouthwestern.edu (D.J.M.); moschetta{at}negrisud.it (A.M.)

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 7{alpha}-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.

Supplementary key words bile acid metabolism • nuclear receptors • transporters • farnesoid X receptor • fibroblast growth factor 15

Abbreviations: ASBT, apical sodium-dependent bile acid transporter; CYP7A1, cholesterol 7{alpha}-hydroxylase; CYP8B1, sterol 12{alpha}-hydroxylase; FGF15, fibroblast growth factor 15; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; SHP, small heterodimer partner; TCA, taurocholate; TßMCA, tauro-ß-muricholate


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