J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700330-JLR200 on August 24, 2007

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Journal of Lipid Research, Vol. 48, 2664-2672, December 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

Insook Kim*, Sung-Hoon Ahn*, Takeshi Inagaki{dagger}, Mihwa Choi{dagger}, Shinji Ito*, Grace L. Guo1,*, Steven A. Kliewer{dagger} and Frank J. Gonzalez2,*

* Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
{dagger} University of Texas Southwestern Medical Center, Dallas, TX 75390

Published, JLR Papers in Press, August 24, 2007.

1 Present address of G. L. Guo: University of Kansas Medical Center, Kansas City, KS 66160.

2 To whom correspondence should be addressed. e-mail: fjgonz{at}helix.nih.gov

Bile acid concentrations are controlled by a feedback regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examined using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (Fxr{Delta}L) or intestine (Fxr{Delta}IE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in Fxr{Delta}L mice but not Fxr{Delta}IE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1.

Supplementary key words FXR • FGF15 • CYP7A1 • CYP8B1 • liver-specific FXR null mice • intestine-specific FXR null mice

Abbreviations: BW, body weight; CA, cholic acid; DCA, deoxycholic acid; FXR, farnesoid X receptor; LC-MS/MS, liquid chromatography tandem mass spectrometry; MCA, murocholic acid; RT-qPCR, real-time quantitative PCR; TCA, taurocholic acid; TDCA, taurodeoxycholic acid


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