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

Endocrinology. 2002 Jun;143(6):2155-68. doi: 10.1210/endo.143.6.8855.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • CD36 Antigens / genetics*
  • Carrier Proteins*
  • Cell Line
  • DNA Primers
  • DNA-Binding Proteins / genetics*
  • Electrophoresis
  • Estradiol / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Humans
  • In Situ Hybridization
  • Lipoproteins, HDL*
  • Luciferases
  • Membrane Proteins*
  • Mutagenesis, Site-Directed
  • Promoter Regions, Genetic / genetics
  • RNA-Binding Proteins*
  • Receptors, Immunologic*
  • Receptors, Lipoprotein / genetics*
  • Receptors, Scavenger
  • Scavenger Receptors, Class B
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*
  • Transfection

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CD36 Antigens
  • Carrier Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • Lipoproteins, HDL
  • Membrane Proteins
  • RNA-Binding Proteins
  • Receptors, Immunologic
  • Receptors, Lipoprotein
  • Receptors, Scavenger
  • SCARB1 protein, human
  • SREBF1 protein, human
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • high density lipoprotein receptors
  • high density lipoprotein binding protein
  • Estradiol
  • Luciferases