Submitted on May 8, 2007
Accepted on August 4, 2007
An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation of LXR
Quan Shang1, Luxing Pan2, Monica Saumoy1, John Y.L. Chiang3, G Stephen Tint4, Gerald E. Salen5, and Guorong Xu6*
1 Medicine, UMD-New Jersey Medical School, Newark, New Jersey, United States
2 Medicine, UND New Jersey Medical School, Newark, New Jersey, United States
3 Biochemistry &Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio, United States
4 Medicine, VA Medical Center, East Orange, New Jersey, United States
5 Gastroenterology, UMDNJ-New Jersey Medical School, Newark, New Jersey, United States
6 Medicine, UMD-New Jersey Medical School, Newark, New Jersey, United States; Medicine, VA Medical Center, East Orange, New Jersey, United States
* To whom correspondence should be addressed. E-mail: xugu{at}umdnj.edu.
The aim of this study was to explore why in rabbits activation of FXR is dominant over activated LXR
in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found an FTF binding element embedded within the LXR binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXR for binding to LXRE. SHP (short heterodimer partner) 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. Gel shift and ChIP assays demonstrated that SHP with FTF diminished LXR 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-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXR from recruiting to LXRE. Therefore, activation of FXR, which up-regulates SHP expression will eliminate the stimulatory effect of LXR on the CYP7A1 promoter because increased levels of SHP combined with FTF diminish the recruitment of LXR to CYP7A1 promoter.
