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Journal of Lipid Research, Vol. 45, 1197-1206, July 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Rapid Communication

The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter

Lita A. Freeman¹, Arion Kennedy, Justina Wu, Samantha Bark, Alan T. Remaley, Silvia Santamarina-Fojo and H. Bryan Brewer, Jr.

Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD

¹ To whom correspondence should be addressed. e-mail: litaf{at}mail.nih.gov

ABSTRACT

The ATP binding cassette (ABC) half-transporters ABCG5 and ABCG8 facilitate biliary and intestinal removal of neutral sterols. Here, we identify a binding site for the orphan nuclear receptor liver receptor homolog-1 (LRH-1) at nt 134–142 of the ABCG5/ABCG8 intergenic region necessary for the activity of both the ABCG5 and ABCG8 promoters. Mutating this LRH-1 binding site reduced promoter activity of the human ABCG5/ABCG8 intergenic region more than 7-fold in HepG2 and Caco2 cells. Electrophoretic mobility shift assays with HepG2 nuclear extracts demonstrated specific binding of LRH-1 to the LRH-1 binding motif in the human ABCG5/ABCG8 intergenic region. LRH-1 overexpression increased promoter activity up to 1.6-fold and 3-fold in Caco2 and 293 cells, respectively. Finally, deoxycholic acid repressed the ABCG5 and ABCG8 promoters, consistent with bile acid regulation via the farnesoid X receptor-small heterodimeric partner-LRH-1 pathway.

These results demonstrate that LRH-1 is a positive transcription factor for ABCG5 and ABCG8 and, in conjunction with studies on LRH-1 activation of other promoters, identify LRH-1 as a "master regulator" for genes involved in sterol and bile acid secretion from liver and intestine.

Abbreviations: ABC, ATP binding cassette; DCA, deoxycholic acid; EMSA, electrophoretic mobility shift assay; FCS, fetal calf serum; FXR, farnesoid X receptor; LRH-1, liver receptor homolog-1; LXR, liver X receptor; SF-1, steroidogenic factor-1; SHP, small heterodimeric partner

Supplementary key words ATP binding cassette transporter • CPF • liver receptor homolog-1 • FTF • FXR • SHP • sitosterolemia • cholesterol • bile acids

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