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J. Biol. Chem., Vol. 277, Issue 52, 50491-50496, December 27, 2002
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From the We investigated the roles of hydrophobic
deoxycholic acid (DCA) and hydrophilic ursocholic acid (UCA) in the
regulation of the orphan nuclear farnesoid X receptor (FXR) in
vivo. Rabbits with bile fistula drainage (removal of the
endogenous bile acid pool), rabbits with bile fistula drainage and
replacement with either DCA or UCA, and intact rabbits fed 0.5%
cholic acid (CA) (enlarged endogenous bile acid pool) were
studied. After bile fistula drainage, cholesterol 7
Regulation of the Farnesoid X Receptor (FXR) by Bile Acid
Flux in Rabbits*
§¶,
,,,§, and§
Medical Service, Veterans Affairs Medical
Center, East Orange, New Jersey 07018, the § Department
of Medicine, University of Medicine and Dentistry of New Jersey, New
Jersey Medical School, Newark, New Jersey 07103, the
Department of Molecular Medicine, The City of Hope National
Medical Center, Duarte, California 91010, and the
** Department of Medicine, University of California, San
Francisco and the Veterans Affairs Medical Center,
San Francisco, California 94121
-hydroxylase
(CYP7A1) mRNA and activity levels increased, FXR-mediated
transcription was decreased, and FXR mRNA and nuclear protein
levels declined. Replacing the enterohepatic bile acid pool with DCA
restored FXR mRNA and nuclear protein levels and activated
FXR-mediated transcription as evidenced by the increased expression of
its target genes, SHP and BSEP, and decreased
CYP7A1 mRNA level and activity. Replacing the bile acid pool with
UCA also restored FXR mRNA and nuclear protein levels but did not
activate FXR-mediated transcription, because the SHP mRNA level and
CYP7A1 mRNA level and activity were unchanged. Feeding CA to intact
rabbits expanded the bile acid pool enriched with the FXR high affinity
ligand, DCA. FXR-mediated transcription became activated as shown by
increased SHP and BSEP mRNA levels and decreased CYP7A1 mRNA
level and activity but did not change FXR mRNA or nuclear protein
levels. Thus, both hydrophobic and hydrophilic bile acids are effective
in maintaining FXR mRNA and nuclear protein levels. However, the
activating ligand (DCA) in the enterohepatic flux is necessary for
FXR-mediated transcriptional regulation, which leads to down-regulation
of CYP7A1.
*
This study was supported by grants from the Department of
Veterans Affairs Research Service, Washington, D. C. and National Institutes of Health Grants DK56830, HL18094, DK57636, DK26756, and
HD20632.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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