Basic–Liver, Pancreas, and Biliary TractOrgan-specific alterations in RARα:RXRα abundance regulate rat Mrp2 (Abcc2) expression in obstructive cholestasis☆,☆☆,★
Section snippets
Materials
Cell culture medium and reagents were obtained from Gibco Life Technologies, Inc. (Gaithersburg, MD). Mouse recombinant tumor necrosis factor α (TNFα) and IL-1β were obtained from R&D Systems (Minneapolis, MN). Chenodeoxycholic acid (CDCA) was obtained from Sigma (St. Louis, MO). The synthetic RXRα ligand, LG364, was provided by Dr. P. Heyman (Ligand Pharmaceuticals, San Diego, CA). RXRα (catalog no. sc-553), RARα (catalog no. sc-551), and SH-PTP1 (catalog no. sc-287) polyclonal antibodies were
Obstructive cholestasis reduces liver, but not kidney, expression of Mrp2
Prior studies from our laboratory and others have shown suppression of Mrp2 RNA and protein expression in the liver in obstructive cholestasis.7, 21, 22, 23 We performed RPA by using total RNA from liver and kidney of rats subjected to BDL for 1, 3, and 14 days to determine whether changes in Mrp2 expression in this model were organ specific. As shown in Figure 1, we confirmed that Mrp2 RNA expression was reduced in liver after BDL, to 66% ± 22% of sham levels by day 3, and to 44% ± 8% of sham
Discussion
The multidrug resistance protein 2 (Mrp2 or Abcc2) is the principal hepatic canalicular multispecific organic anion transporter, and it mediates excretion of bilirubin-diglucuronide and a variety of conjugates of lipophilic substances via bile under normal conditions. Our group and others have previously characterized down-regulation of hepatic Mrp2 RNA and protein expression and function in experimental models of cholestatic liver disease.7, 21, 22, 23 More recently, we and other investigators
References (32)
- et al.
Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat
Gastroenterology
(2001) - et al.
Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone
Gastroenterology
(1999) - et al.
The rat canalicular conjugate export pump (mrp2) is down-regulated in intrahepatic and obstructive cholestasis
Gastroenterology
(1997) - et al.
Up-regulation of transporters of the mrp family by drugs and toxins
Toxicol Lett
(2001) - et al.
Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver
Gastroenterology
(2001) - et al.
Regulation of multidrug resistance-associated protein 2 (abcc2) by the nuclear receptors pregnane x receptor, farnesoid x-activated receptor, and constitutive androstane receptor
J Biol Chem
(2002) - et al.
Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation
J Biol Chem
(2000) - et al.
Kupffer cell-mediated down regulation of rat hepatic cmoat/mrp2 gene expression
Biochem Biophys Res Commun
(1999) - et al.
Interleukin-1 receptor type i gene-deficient bile duct-ligated mice are partially protected against endotoxin
Hepatology
(2002) - et al.
Orphan nuclear receptors as elixirs and fixers of sterol metabolism
J Biol Chem
(2001)
The acute phase response is associated with retinoid x receptor repression in rodent liver
J Biol Chem
Bile acid concentrations in human and rat liver tissue and in hepatocyte nuclei
Gastroenterology
Stress pathway activation induces phosphorylation of retinoid x receptor
J Biol Chem
Dimerization with retinoid x receptors and phosphorylation modulate the retinoic acid-induced degradation of retinoic acid receptors alpha and gamma through the ubiquitin-proteasome pathway
J Biol Chem
Hyperphosphorylation of the retinoid x receptor alpha by activated c-jun nh2-terminal kinases
J Biol Chem
Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver
Hepatology
Cited by (0)
- ☆
Address requests for reprints to: Lee A. Denson, M.D., Yale Child Health Research Center, Department of Pediatrics, 464 Congress Avenue, P.O. Box 208081, New Haven, Connecticut 06520-8081. e-mail: [email protected]; fax: (203) 737-5972.
- ☆☆
Supported by National Institutes of Health grant DK02700 (to L.A.D.), DK25636 (to J.L.B.), Charles H. Hood Foundation (to L.A.D.), and Yale Liver Center (DK P30-34989).
- ★
The authors acknowledge the excellent technical support of Himmat Bajwa.