IDENTIFICATION OF DIAZEPAM-BINDING INHIBITOR ACYL-COA-BINDING PROTEINAS A STEROL REGULATORY ELEMENT-BINDING PROTEIN-RESPONSIVE GENE/

Diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP), a high ly conserved 10-kDa polypeptide, has been implicated in various physio logical processes including gamma-aminobutyric acid type A receptor bi nding, acyl-CoA binding and transport, steroidogenesis, and peptide ho rmone release. Both in LNCaP prostate cancer cells and 3T3-L1 preadipo cytes, the expression of DBI/ACBP is stimulated under conditions that promote lipogenesis (treatment with androgens and insulin, respectivel y) and that involve the activation of sterol regulatory element-bindin g proteins (SREBPs), Accordingly, we investigated whether DBI/ACBP exp ression is under the direct control of SREBPs, Analysis of the human a nd rat DBI/ACBP promoter revealed the presence of a conserved sterol r egulatory element (SRE)-like sequence. Gel shift analysis confirmed th at this sequence is able to bind SREBPs, In support of the functionali ty of SREBP binding, coexpression of SREBP-1a with a DBI/ACBP promoter -reporter gene resulted in a 50-fold increase in transcriptional activ ity in LNCaP cells. Disruption of the SRE decreased basal expression a nd abolished SREBP-1a-induced transcriptional activation. In agreement with the requirement of a co-regulator for SREBP function, transcript ional activation by SREBP-1a overexpression was severely diminished wh en a neighboring NF-Y site was mutated. Cholesterol depletion or andro gen treatment, conditions that activate SREBP function in LNCaP cells, led to an increase in DBI/ACBP mRNA expression and SRE-dependent tran scriptional activation. These findings indicate that the promoter for DBI/ACBP contains a functional SRE that allows DBI/ACBP to be coregula ted with other genes involved in lipid metabolism.