Abstract
Background & Aims: Obstructive cholestasis is associated with adaptive changes in expression of hepatocyte transport proteins. These include a significant reduction in hepatic expression of Mrp2 (Abcc2), the principal canalicular multispecific organic anion transporter. Renal Mrp2 expression is preserved under these conditions. We have recently reported that the rat Mrp2 promoter is activated by RARα:RXRα, and that interleukin 1β (IL-1β) repressed promoter activity via this element. We hypothesized that cytokines, which are up-regulated in obstructive cholestasis, would reduce nuclear RARα:RXRα levels, and that this would be associated with suppression of hepatic Mrp2 expression. Methods: Male Sprague-Dawley rats were subjected to bile duct ligation (BDL) or sham surgery, and liver and kidney RNA and protein were isolated. Primary rat hepatocytes were treated with bile acids, retinoids, or cytokines, and RNA and protein were isolated. Mrp2 and RARα:RXRα protein abundance and activity were assessed by using electrophoretic mobility shift assays (EMSA) and immunoblots. IL-1β abundance was determined by enzyme-linked immunosorbent assay. RARα, RXRα, and Mrp2 RNA levels were determined by using ribonuclease protection assays (RPA). Results: Mrp2 down-regulation and IL-1β up-regulation were observed in liver after BDL. This was temporally associated with down-regulation of liver RARα:RXRα nuclear protein levels and binding to the Mrp2 promoter cis element. Renal RARα:RXRα and Mrp2 expression were preserved under these conditions. IL-1β treatment of primary hepatocytes reduced Mrp2 and RXRα expression. Conclusions: Organ-specific regulation of Mrp2 expression in obstructive cholestasis is associated with cytokine-dependent alterations in RARα:RXRα nuclear receptors. Preservation of renal Mrp2 expression may permit urinary excretion of toxic organic anions and xenobiotics under conditions in which biliary excretion is impaired.GASTROENTEROLOGY 2002;123:599-607
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