Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome p450

Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The po tency and hierarchy of bile acids as ligands for the farnesyl/ bile acid re ceptor (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyt e cultures. FXR:RXR heterodimers bound to IR1 elements and enhanced bile ac id transcriptional activation of the mouse and human BSEP/SPGP promoters. I n FXR/BAR nullizygous mice, which have dramatically reduced BSEP/SPGP level s, hepatic CYP3A11 and CYP2B10 were strongly but unexpectedly induced. Nota bly, the rank order of bile acids as CYP3A4 inducers and activators of preg nane X receptor/steroid and xenobiotic receptor (PXR/SXR) closely parallele d 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 hepatotoxi city, activates PXR and efficaciously induces CYP3A4 (a bile-metabolizing e nzyme) in primary human hepatocytes thus providing one mechanism for its he patoprotection. Because serum and urinary bile acids increased in FXR/BAR - /- mice, we evaluated hepatic transporters for compensatory changes that mi ght circumvent the profound decrease in BSEP/SPGP. We found weak MRP3 up-re gulation. In contrast, MRP4 was substantially increased in the FXR/ BAR nul lizygous mice and was further elevated by cholic acid. Thus, enhanced hepat ocellular concentrations of bile acids, due to the down-regulation of BSEP/ SPGP-mediated efflux in FXR nullizygous mice, result in an alternate but ap parent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporter s that is consistent with activation of PXR/SXR by bile acids.