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Am J Physiol Gastrointest Liver Physiol 293: G817-G823, 2007. First published August 9, 2007; doi:10.1152/ajpgi.00209.2007
0193-1857/07 $8.00
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LIVER AND BILIARY TRACT

An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXR{alpha}

Quan Shang,1 Luxing Pan,2 Monica Saumoy,1 John Y. L. Chiang,3 G. Stephen Tint,1,2 Gerald Salen,1 and Guorong Xu1,2

1Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey; 2Medical Research Service, Veterans Affairs Medical Center, East Orange, New Jersey; 3Department of Biochemistry and Molecular Pathology, Northeastern Ohio University College of Medicine, Rootstown, Ohio

Submitted 8 May 2007 ; accepted in final form 4 August 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.

cholesterol 7{alpha}-hydroxylase; regulation; LXR binding site; short heterodimer partner; fetoprotein transcription factor; farnesoid X receptor; liver X receptor-{alpha}


Address for reprint requests and other correspondence: G. Xu, GI Lab (15A), VA Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095 (e-mail: xugu{at}umdnj.edu)






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