Changes of organic anion transporter MRP4 and related nuclear receptors in human obstructive cholestasis

J Gastrointest Surg. 2011 Jun;15(6):996-1004. doi: 10.1007/s11605-011-1473-2. Epub 2011 Feb 26.

Abstract

Background: Hepatic multidrug resistance-associated protein 4 (Mrp4) levels are low, but increase markedly in rodent cholestatic liver. Nuclear receptors (NRs) are essential for regulating Mrp4 expression in cholestasis models. However, information about MRP4 and related NRs, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoic X receptor-α (RXRα), is relatively lacking in human obstructive cholestasis. We collected liver samples from patients with obstructive cholestasis or without liver disease and investigated the expression of MRP4 and NRs CAR, PXR, and RXRα by semi-quantitative RT-PCR, Western blot and immunostaining assays.

Results: MRP4 mRNA/protein levels were markedly increased in obstructive cholestasis. Concentration of serum total bile acids (TBA) was significantly correlated with MRP4 protein in cholestasis samples (P < 0.01). PXR and RXRα mRNA/protein levels were significantly increased in obstructive cholestasis. CAR mRNA levels were unchanged while protein levels were markedly induced in obstructive cholestasis. There was a statistically positive correlation between MRP4 mRNA and CAR protein (P < 0.05), suggesting that CAR may activate transcription of MRP4 genes by its nuclear translocation.

Conclusion: Hepatic MRP4 levels were dramatically induced in human obstructive cholestasis, which may reduce liver injury by increasing efflux of toxic bile acids from hepatocytes into blood.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Acids and Salts / blood
  • Bilirubin / blood
  • Blotting, Western
  • Cholestasis, Extrahepatic / metabolism*
  • Common Bile Duct / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression
  • Humans
  • Liver / metabolism*
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Pregnane X Receptor
  • RNA, Messenger / metabolism*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Retinoid X Receptor alpha / genetics
  • Retinoid X Receptor alpha / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • ABCC4 protein, human
  • Bile Acids and Salts
  • Multidrug Resistance-Associated Proteins
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Retinoid X Receptor alpha
  • constitutive androstane receptor
  • Bilirubin