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J Biol Chem, Vol. 275, Issue 12, 8835-8843, March 24, 2000
From the Cytokines have been implicated in the
pathogenesis of inflammatory cholestasis. This is due to
transcriptional down-regulation of hepatic transporters including the
Na+/bile acid cotransporter, ntcp, and
the multispecific organic anion exporter, mrp2. We have
recently shown that ntcp suppression by lipopolysaccharide
in vivo is caused by down-regulation of transactivators
including the previously uncharacterized Footprint B-binding protein.
Both the ntcp FpB element and the mrp2 promoter contain potential retinoid-response elements. We hypothesized that
retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers
would activate these two genes and that cytokines that reduce bile flow
might do so by suppressing nuclear levels of these transactivators.
Retinoid transactivation and interleukin-1
Interleukin-1
Suppresses Retinoid Transactivation of Two
Hepatic Transporter Genes Involved in Bile Formation*
,,,,¶
Department of Pediatrics, Yale University
School of Medicine, New Haven, Connecticut 06520 and the
§ Howard Hughes Medical Institute and the Department of
Pharmacology, University of Texas Southwestern Medical Center,
Dallas, Texas 75235-9050
down-regulation of the
ntcp and mrp2 promoters were mapped to RXR
:RAR-response elements. Gel mobility shift assays demonstrated specific binding of RXR:RAR heterodimers to the ntcp
and mrp2 retinoid-response elements. The RXR:RAR
complex was down-regulated by IL-1 in HepG2 cells. An unexpected
finding was that an adjacent CAAT-enhancer-binding protein element was
required for maximal transactivation of the ntcp promoter
by RXR:RAR. Taken together, these studies demonstrate regulation
of two hepatobiliary transporter genes by RXR:RAR and describe a
mechanism which likely contributes to their down-regulation during inflammation.
*
This work was supported by Grant DK-02318 from the National
Institutes of Health and the Yale Child Health Research Center (to
S. J. K.), Grant HD-07388 from the National Institutes of Health (to L. A. D.), and from the HHMI (to D. J. M.).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.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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