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

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 b...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-03, Vol.275 (12), p.8835-8843
Main Authors: Denson, L A, Auld, K L, Schiek, D S, McClure, M H, Mangelsdorf, D J, Karpen, S J
Format: Article
Language:English
Subjects:
Albumins - genetics
Animals
Anion Transport Proteins
Bile - metabolism
Carrier Proteins - biosynthesis
Carrier Proteins - genetics
Cholestasis - etiology
Cytokines - pharmacology
Dimerization
DNA-Binding Proteins - metabolism
Humans
Interleukin-1 - pharmacology
Interleukin-6 - genetics
Liver - metabolism
Membrane Transport Proteins
Mutation
Nuclear Proteins - metabolism
Organic Anion Transporters, Sodium-Dependent
Promoter Regions, Genetic
Protein Binding
Protein Isoforms - metabolism
Rats
Receptors, Retinoic Acid - metabolism
Recombinant Fusion Proteins - biosynthesis
Response Elements
Retinoid X Receptors
Retinoids - pharmacology
Symporters
Transcription Factors - metabolism
Transcriptional Activation
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Summary: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-1beta down-regulation of the ntcp and mrp2 promoters were mapped to RXRalpha:RARalpha-response elements. Gel mobility shift assays demonstrated specific binding of RXRalpha:RARalpha heterodimers to the ntcp and mrp2 retinoid-response elements. The RXRalpha:RARalpha complex was down-regulated by IL-1beta 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 RXRalpha:RARalpha. Taken together, these studies demonstrate regulation of two hepatobiliary transporter genes by RXRalpha:RARalpha and describe a mechanism which likely contributes to their down-regulation during inflammation.
ISSN:0021-9258