The Small Heterodimer Partner Interacts with the Pregnane X Receptor and Represses Its Transcriptional Activity

• DOI: 10.1210/me.2002-0383
• Publication Date: 2003-06-16T20:24:34Z
• Authors: Jean Claude Ourlin; Fredéric Lasserre; Thierry Pineau; Jean Michel Fabre; Antonio Sa-Cunha; Patrick Maurel; Marie-José Vilarem; Jean Marc Pascussi
• Keywords: Pregnane X receptor; Small heterodimer partner; Farnesoid X receptor; Chenodeoxycholic acid; CYP8B1; Corepressor; Constitutive androstane receptor; CYP3A

SHP (small heterodimer partner, NR1I0) is an atypical orphan member of the nuclear receptor subfamily in that it lacks a DNA-binding domain. It mostly expressed liver, where binds to and inhibits function receptors. up-regulated by primary bile acids, through activation their farnesoid X receptor, leading repression cholesterol 7α-hydroxylase (CYP7α) expression, rate-limiting enzyme acid production from cholesterol. PXR (pregnane NR1I2) broad-specificity sensor recognizes wide variety synthetic drugs as well endogenous compounds such precursors. Upon activation, induces CYP3A CYP7α, suggesting can act on both synthesis elimination. Indeed, CYP7α are involved biochemical pathways conversion into whereas also detoxification toxic secondary derivatives. Here, we show target for SHP. Using pull-down assays, interacts with murine human ligand-dependent manner. From transient transfection shown be potent repressor transactivation. Furthermore, report chenodeoxycholic cholic acid, two ligands, induce up-regulation provoke PXR-mediated induction hepatocytes vivo mice. These results reveal elaborate regulatory cascade, tightly controlled SHP, maintenance liver.