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

• 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
• ISSN: 0021-9258

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.