Interleukin-1β suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation

Lee A. Denson, Kathryn L. Auld, Dagmar S. Schiek, Mitchell H. McClure, David J. Mangelsdorf, Saul J. Karpen

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

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-1β down-regulation of the ntcp and mrp2 promoters were mapped to RXRα:RARα- response elements. Gel mobility shift assays demonstrated specific binding of RXRα: RARα heterodimers to the ntcp and mrp2 retinoid-response elements. The RXRα:RARα complex was downregulated by IL-1β 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 RXRα:RARα. Taken together, these studies demonstrate regulation of two hepatobiliary transporter genes by RXRα:RARα and describe a mechanism which likely contributes to their down-regulation during inflammation.

Original languageEnglish (US)
Pages (from-to)8835-8843
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number12
DOIs
StatePublished - Mar 24 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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