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J. Biol. Chem., Vol. 277, Issue 34, 30559-30566, August 23, 2002
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From the Laboratory of Molecular Gastroenterology and Hepatology
and the Division of Clinical Pharmacology and Toxicology, University
Hospital, CH-8091 Zurich, Switzerland
The apical sodium-dependent bile salt
transporter (ASBT/SLC10A2), also called
the ileal bile acid transporter, mediates the intestinal
absorption of bile salts. The efficiency of this transport process is a
determinant of hepatic bile salt synthesis from cholesterol and of
serum triglyceride levels. Our aim was to characterize the human
ASBT gene promoter with respect to regulatory mechanisms that coordinately affect ASBT expression and hepatic lipid and bile
salt metabolism. The minimal construct that confers full promoter
activity contains three functional hepatocyte nuclear factor 1
Human Apical Sodium-dependent Bile Salt Transporter
Gene (SLC10A2) Is Regulated by the Peroxisome
Proliferator-activated Receptor
*
(HNF1) recognition sites, explaining the dependence of
ASBT gene expression upon HNF1. A nuclear receptor
binding site arranged as a direct hexanucleotide repeat (DR1 motif) is localized ~1.6 kb upstream of the transcription initiation site. Constructs containing this element were transactivated by WY14643 and
ciprofibrate, ligands of the peroxisome proliferator-activated receptor
(PPAR), in Caco2 cells. The DR1 element was shown to bind the
PPAR/9-cis-retinoic acid receptor heterodimer, and targeted mutagenesis of the DR1 motif abolished PPAR responsiveness. Ciprofibrate treatment of SK-ChA cholangiocytes increased ASBT mRNA levels, suggesting a physiologic role for PPAR-mediated ASBT gene regulation. This study identifies PPAR as a
novel link between ileal bile salt absorption and hepatic lipid metabolism.
*
This work was supported by Grants 32-59155.99 and 632-062773 from the Swiss National Science Foundation, Bern,
Switzerland.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.
To whom correspondence should be addressed: Division of
Gastroenterology and Hepatology, University Hospital, CH-8091 Zurich, Switzerland. Tel.: 41-1-255-4097; Fax: 41-1-255-4598; E-mail: gerd.kullak@dim.usz.ch.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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