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Freeman, L.A. et al.

Freeman, Kennedy, Wu, Bark, Remaley, Santamarina-Fojo, Brewer,

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

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.[1]

References

The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter. Freeman, L.A., Kennedy, A., Wu, J., Bark, S., Remaley, A.T., Santamarina-Fojo, S., Brewer, H.B. J. Lipid Res. (2004) [Pubmed]

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