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

An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXR alpha. Am J Physiol Gastrointest Liver Physiol 293: G817-G823, 2007. First published August 9, 2007; doi:10.1152/ajpgi.00209.2007.-The aim of this study was to explore why in rabbits activation of farnesoid X receptor (FXR) is dominant over activated liver X receptor-alpha (LXR alpha) in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found a fetoprotein transcription factor (FTF) binding element embedded within the LXR alpha binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXR alpha 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 LXR alpha. Gel shift and chromatin immunoprecipitation assays demonstrated that SHP with FTF diminished LXR alpha\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 LXR alpha-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXR alpha from recruiting to LXRE. Therefore, activation of FXR, which upregulates SHP expression, will eliminate the stimulatory effect of LXR alpha on the CYP7A1 promoter because increased levels of SHP combined with FTF diminish the recruitment of LXR alpha to CYP7A1 promoter.