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DAX-1 Represses the High-Density Lipoprotein Receptor Through Interaction with Positive Regulators Sterol Regulatory Element-Binding Protein-1a and Steroidogenic Factor-1

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

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

The high-density lipoprotein receptor (HDL-R) mediates the selective uptake of high-density lipoprotein cholesterol in nonplacental steroidogenic tissues. We have previously demonstrated that sterol regulatory element-binding protein-1a (SREBP-1a) and steroidogenic factor-1 (SF-1) positively regulate HDL-R gene transcription. In the present study, we examined whether DAX-1 (dosage-sensitive sex adrenal hypoplasia congenital critical region on the X chromosome, gene-1) could influence the expression of the HDL-R gene. Cotransfection studies demonstrated that DAX-1 was able to repress SREBP-1a and SF-1-dependent activation of the HDL-R promoter. Mammalian two-hybrid assays demonstrated that DAX-1 could interact with SREBP-1a. In addition, electrophoretic mobility shift assays demonstrated that initial incubation of DAX-1 with SREBP-1a protein in the absence of DNA prevented subsequent binding of SREBP-1a to the HDL-R sterol regulatory elements in a dose-dependent manner, whereas, in the case of SF-1, DAX-1 formed a complex with SF-1 protein on the DNA. These data suggest that DAX-1 inhibits SREBP-1a- and SF-1-dependent activation of the HDL-R promoter through different mechanisms. This investigation confirms that DAX-1 has an important role in regulating steroidogenesis by interfering with SREBP-1a and SF-1 induction of a gene involved in the transport of cholesterol, thereby limiting the amount of substrate available for steroid hormone production.

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