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Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout

Mahfoud Assem1, Erin G Schuetz, Markos Leggas

  • 1Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

The Journal of Biological Chemistry
|March 9, 2004
PubMed

Insights

The study reveals that Mrp4 and Sult2a1 form a pathway to eliminate sulfated steroids and bile acids from the liver. This compensatory mechanism is crucial for liver protection, especially during cholestasis.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Drug Metabolism

Background:

  • The ATP-binding cassette (ABC) transporter, Mrp4, is known to transport sulfated steroids like DHEA-s.
  • Sulfated bile acids exhibit high-affinity interaction with Mrp4.
  • Hepatic Mrp4 levels are typically low but increase during cholestatic conditions, suggesting a protective role.

Purpose of the Study:

  • To investigate the compensatory mechanism of Mrp4 up-regulation during cholestasis.
  • To elucidate the role of the nuclear receptor CAR in regulating Mrp4 and Sult2a1 expression.
  • To understand the integrated pathway for eliminating sulfated steroid and bile acid metabolites from the liver.

Main Methods:

  • Assessed Mrp4 and Sult2a1 expression in primary human hepatocytes and HepG2 cells.
  • Utilized Mrp4-null mice to examine gene expression interdependencies.
  • Investigated the effect of CAR activators on hepatic gene expression.

Main Results:

  • Hepatic Mrp4 levels increase under cholestatic conditions, indicating a compensatory response.
  • The nuclear receptor CAR is essential for the coordinated up-regulation of hepatic Mrp4 and Sult2a1.
  • CAR activators enhanced Mrp4 and Sult2a1 expression in human liver cells.
  • Sult2a1 expression was reduced in Mrp4-null mice, highlighting a relationship between Mrp4 and Sult2a1.

Conclusions:

  • Mrp4 and Sult2a1 are involved in an integrated pathway for the elimination of sulfated steroid and bile acid metabolites.
  • This pathway plays a vital role in protecting the liver from the accumulation of hydrophobic bile acids during cholestasis.

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