Faculty Collaboration Database

Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem 2001 Oct 19;276(42):39411-8

Date

08/18/2001

Pubmed ID

11509573

DOI

10.1074/jbc.M106340200

Scopus ID

2-s2.0-0035914467 (requires institutional sign-in at Scopus site)   358 Citations

Abstract

Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The potency and hierarchy of bile acids as ligands for the farnesyl/bile acid receptor (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyte cultures. FXR:RXR heterodimers bound to IR1 elements and enhanced bile acid transcriptional activation of the mouse and human BSEP/SPGP promoters. In FXR/BAR nullizygous mice, which have dramatically reduced BSEP/SPGP levels, hepatic CYP3A11 and CYP2B10 were strongly but unexpectedly induced. Notably, the rank order of bile acids as CYP3A4 inducers and activators of pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR) closely paralleled each other but was markedly different from their hierarchy and potency as inducers of BSEP in human hepatocytes. Moreover, the hepatoprotective bile acid ursodeoxycholic acid, which reverses hydrophobic bile acid hepatotoxicity, activates PXR and efficaciously induces CYP3A4 (a bile-metabolizing enzyme) in primary human hepatocytes thus providing one mechanism for its hepatoprotection. Because serum and urinary bile acids increased in FXR/BAR -/- mice, we evaluated hepatic transporters for compensatory changes that might circumvent the profound decrease in BSEP/SPGP. We found weak MRP3 up-regulation. In contrast, MRP4 was substantially increased in the FXR/BAR nullizygous mice and was further elevated by cholic acid. Thus, enhanced hepatocellular concentrations of bile acids, due to the down-regulation of BSEP/SPGP-mediated efflux in FXR nullizygous mice, result in an alternate but apparent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporters that is consistent with activation of PXR/SXR by bile acids.

Author List

Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, Venkataramanan R, Cai H, Sinal CJ, Gonzalez FJ, 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

ATP-Binding Cassette Transporters
Amino Acid Sequence
Animals
Base Sequence
Bile Acids and Salts
Cell Line
Cell Nucleus
Cells, Cultured
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System
Dimerization
Dose-Response Relationship, Drug
Down-Regulation
Genes, Reporter
Hepatocytes
Humans
Immunoblotting
Ligands
Liver
Luciferases
Mice
Mice, Inbred BALB C
Mice, Transgenic
Mixed Function Oxygenases
Molecular Sequence Data
Multidrug Resistance-Associated Proteins
Plasmids
Promoter Regions, Genetic
Protein Binding
Protein Structure, Tertiary
Reverse Transcriptase Polymerase Chain Reaction
Ribosomal Proteins
Sequence Homology, Nucleic Acid
Transfection
Up-Regulation
Ursodeoxycholic Acid