An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXRα

The aim of this study was to explore why in rabbits activation of farnesoid X receptor (FXR) is dominant over activated liver X receptor-α (LXRα) in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found a fetoprotein transcription factor (FTF) binding element embedded within the LXRα binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXRα for binding to LXRE. Short heterodimer partner (SHP) enhances the competitive ability of FTF. Studies in HepG2 cells showed that SHP combined with FTF had more powerful effect to offset the stimulation of CYP7A1 by LXRα. Gel shift and chromatin immunoprecipitation assays demonstrated that SHP with FTF diminished LXRα binding to the CYP7A1 promoter. In vivo studies in rabbits fed cholesterol for 10 days showed that hepatic expression of SHP but not FTF rose and LXRα-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXRα from recruiting to LXRE. Therefore, ac...