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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
12
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pubmed:dateCreated |
2000-4-27
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Albumins,
http://linkedlifedata.com/resource/pubmed/chemical/Anion Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-6,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Transport Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Organic Anion Transporters...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Isoforms,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Retinoic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoid X Receptors,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoids,
http://linkedlifedata.com/resource/pubmed/chemical/Symporters,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/sodium-bile acid cotransporter
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
24
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pubmed:volume |
275
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8835-43
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pubmed:dateRevised |
2010-8-9
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pubmed:meshHeading |
pubmed-meshheading:10722729-Albumins,
pubmed-meshheading:10722729-Animals,
pubmed-meshheading:10722729-Anion Transport Proteins,
pubmed-meshheading:10722729-Bile,
pubmed-meshheading:10722729-Carrier Proteins,
pubmed-meshheading:10722729-Cholestasis,
pubmed-meshheading:10722729-Cytokines,
pubmed-meshheading:10722729-DNA-Binding Proteins,
pubmed-meshheading:10722729-Dimerization,
pubmed-meshheading:10722729-Humans,
pubmed-meshheading:10722729-Interleukin-1,
pubmed-meshheading:10722729-Interleukin-6,
pubmed-meshheading:10722729-Liver,
pubmed-meshheading:10722729-Membrane Transport Proteins,
pubmed-meshheading:10722729-Mutation,
pubmed-meshheading:10722729-Nuclear Proteins,
pubmed-meshheading:10722729-Organic Anion Transporters, Sodium-Dependent,
pubmed-meshheading:10722729-Promoter Regions, Genetic,
pubmed-meshheading:10722729-Protein Binding,
pubmed-meshheading:10722729-Protein Isoforms,
pubmed-meshheading:10722729-Rats,
pubmed-meshheading:10722729-Receptors, Retinoic Acid,
pubmed-meshheading:10722729-Recombinant Fusion Proteins,
pubmed-meshheading:10722729-Response Elements,
pubmed-meshheading:10722729-Retinoid X Receptors,
pubmed-meshheading:10722729-Retinoids,
pubmed-meshheading:10722729-Symporters,
pubmed-meshheading:10722729-Transcription Factors,
pubmed-meshheading:10722729-Transcriptional Activation
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pubmed:year |
2000
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pubmed:articleTitle |
Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation.
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pubmed:affiliation |
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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