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Estrogen Activates the High-Density Lipoprotein Receptor Gene via Binding to Estrogen Response Elements and Interaction with Sterol Regulatory Element Binding Protein-1A

Departments of Obstetrics & Gynecology (D.L., M.D.S., W.S.-E., M.P.M.) and Biochemistry & Molecular Biology (M.P.M.), College of Medicine, University of South Florida, Tampa, Florida 33606

Address all correspondence and requests for reprints to: Dr. Mark P. McLean, Department of Obstetrics & Gynecology, University of South Florida, 4 Columbia Drive, Room 529, Tampa, Florida 33606. E-mail: . mmclean{at}hsc.usf.edu

The effects of E2 on the high-density lipoprotein receptor (HDL-R) scavenger receptor class B type I (SR-BI) gene were examined. Four putative estrogen response element half-site motifs (ERE) (-2176, -1726, -1622, and -1211, designated ERE-1, 2, 3, and 4, respectively) were identified in the HDL-R SR-BI promoter. Transfection studies and mutation analysis demonstrated that E2 significantly increased HDL-R SR-BI promoter activity and that mutating ERE-1, 2, and 4 resulted in a loss of E2 responsiveness. Both ER and ERß formed specific complexes with ERE-1, 2, and 4 but did not bind ERE-3 in vitro. Interestingly, ERE-3 was the motif shown not to be important for E2-activation of the HDL-R SR-BI promoter in the mutational analysis studies. The influence of SREBP-1a (sterol regulatory element binding protein-1a) on E2 regulation of the HDL-R SR-BI gene was also examined. SREBP-1a was able to bind directly to the ERE motifs and enhanced ER binding when both ER subtypes were present. ER and ß also bound to a sterol response element motif, but they did not enhance SREBP-1a binding. Cotransfection studies demonstrated that the presence of the three factors, ER, ERß, and SREBP-1a, enhanced the overall luciferase activity produced from the HDL-R SR-BI promoter construct in the presence of only one of the factors. Interaction of SREBP-1a with both ERs was demonstrated using a mammalian two-hybrid assay. The data confirmed that E2 through the ERs can positively regulate the HDL-R SR-BI through binding and activation of three ERE motifs and identified SREBP-1a as a potential coactivator of the E2-ER-dependent effects on the HDL-R SR-BI gene.

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