Faculty Collaboration Database

Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J Biol Chem 2004 May 21;279(21):22250-7

Date

03/09/2004

Pubmed ID

15004017

DOI

10.1074/jbc.M314111200

Scopus ID

2-s2.0-2542440464 (requires institutional sign-in at Scopus site)   218 Citations

Abstract

The ABC transporter, Mrp4, transports the sulfated steroid DHEA-s, and sulfated bile acids interact with Mrp4 with high affinity. Hepatic Mrp4 levels are low, but increase under cholestatic conditions. We therefore inferred that up-regulation of Mrp4 during cholestasis is a compensatory mechanism to protect the liver from accumulation of hydrophobic bile acids. We determined that the nuclear receptor CAR is required to coordinately up-regulate hepatic expression of Mrp4 and an enzyme known to sulfate hydroxy-bile acids and steroids, Sult2a1. CAR activators increased Mrp4 and Sult2a1 expression in primary human hepatocytes and HepG2, a human liver cell line. Sult2a1 was down-regulated in Mrp4-null mice, further indicating an inter-relation between Mrp4 and Sult2a1 gene expression. Based on the hydrophilic nature of sulfated bile acids and the Mrp4 capability to transport sulfated steroids, our findings suggest that Mrp4 and Sult2a1 participate in an integrated pathway mediating elimination of sulfated steroid and bile acid metabolites from the liver.

Author List

Assem M, Schuetz EG, Leggas M, Sun D, Yasuda K, Reid G, Zelcer N, Adachi M, Strom S, Evans RM, Moore DD, Borst P, Schuetz JD

Author

Mahfoud Assem PharmD Associate Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bile Acids and Salts
Blotting, Western
Cell Line
Cholestasis
Enhancer Elements, Genetic
Gene Expression Regulation
Genes, Reporter
Genotype
Green Fluorescent Proteins
Hepatocytes
Humans
Hydroxy Acids
Immunohistochemistry
Ligands
Liver
Luminescent Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Models, Genetic
Multidrug Resistance-Associated Proteins
NIH 3T3 Cells
Oligonucleotide Array Sequence Analysis
Oligonucleotides
Protein Binding
RNA
Receptors, Cytoplasmic and Nuclear
Retroviridae
Reverse Transcriptase Polymerase Chain Reaction
Steroids
Sulfotransferases
Transcription Factors
Transcription, Genetic
Transfection
Up-Regulation