Estrogen activates the high-density lipoprotein receptor gene via binding to estrogen response elements and interaction with sterol regulatory element binding protein-1A

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 (ERE1/(2)) (-2176, -1726, -1622, and -1211, designated ERE1/(2)-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 ERE1/(2)-1,2, and 4 resulted in a loss of E2 responsiveness. Both ERalpha and ERbeta formed specific complexes with ERE1/(2)-1, 2, and 4 but did not bind ERE1/(2)-3 in vitro. Interestingly, ERE1/(2)-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 ERE1/(2) motifs and enhanced ER binding when both ER subtypes were present. ERalpha and beta 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, ERalpha, ERbeta, 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-la 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 ERE1/(2) motifs and identified SREBP-la as a potential coactivator of the E2-ER-dependent effects on the HDL-R SR-BI gene.