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Identification of Liver Receptor Homolog-1 as a Novel Regulator of Apolipoprotein AI Gene Transcription

GlaxoSmithKline (P.D., E.N.), Cardiovascular & Urogenital Center of Excellence for Drug Discovery, 91951 Les Ulis, France; GlaxoSmithKline, High Throughput Biology (C.M.G., B.G.), and Gene Interference Group (J.E.B.), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Philippe Delerive, GlaxoSmithKline Research and Development, Cardiovascular and Urogenital Diseases Center of Excellence for Drug Discovery, 25 Avenue du Quebec, 91951 Les Ulis, France. E-mail: pxd14884{at}gsk.com.

The orphan nuclear receptor liver receptor homolog-1 (LRH-1) has been reported to play a role in bile acid biosynthesis and reverse cholesterol transport. In this study, we examined the role of LRH-1 in the regulation of the apolipoprotein AI (APOAI) gene. Using RNA interference and adenovirus-mediated overexpression, we show that LRH-1 directly regulates APOAI gene transcription. Transient transfection experiments and EMSAs revealed that LRH-1 directly regulates APOAI transcription by binding to an LRH-1 response element located in the proximal APOAI promoter region. Chromatin immunoprecipitation experiments revealed that LRH-1 binds to the human APO AI promoter in vivo. Finally, we show that the transcriptional repressor SHP (small heterodimer partner) suppressed APOAI gene expression by inhibiting LRH-1 transcriptional activity. Taken together, our results demonstrate that LRH-1 is a novel regulator of APOAI transcription and underscore the role of this receptor in cholesterol homeostasis.

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Nuclear Receptors:   SHP  |  LRH-1

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