Identification of diazepam-binding Inhibitor/Acyl-CoA-binding protein as a sterol regulatory element-binding protein-responsive gene.
Diazepam-binding inhibitor/acyl-CoA-binding protein (DBI/ACBP), a highly conserved 10-kDa polypeptide, has been implicated in various physiological processes including gamma-aminobutyric acid type A receptor binding, acyl-CoA binding and transport, steroidogenesis, and peptide hormone release. Both in LNCaP prostate cancer cells and 3T3-L1 preadipocytes, the expression of DBI/ACBP is stimulated under conditions that promote lipogenesis (treatment with androgens and insulin, respectively) and that involve the activation of sterol regulatory element-binding proteins (SREBPs). Accordingly, we investigated whether DBI/ACBP expression is under the direct control of SREBPs. Analysis of the human and rat DBI/ACBP promoter revealed the presence of a conserved sterol regulatory element (SRE)-like sequence. Gel shift analysis confirmed that this sequence is able to bind SREBPs. In support of the functionality of SREBP binding, coexpression of SREBP-1a with a DBI/ACBP promoter-reporter gene resulted in a 50-fold increase in transcriptional activity in LNCaP cells. Disruption of the SRE decreased basal expression and abolished SREBP-1a-induced transcriptional activation. In agreement with the requirement of a co-regulator for SREBP function, transcriptional activation by SREBP-1a overexpression was severely diminished when a neighboring NF-Y site was mutated. Cholesterol depletion or androgen treatment, conditions that activate SREBP function in LNCaP cells, led to an increase in DBI/ACBP mRNA expression and SRE-dependent transcriptional activation. These findings indicate that the promoter for DBI/ACBP contains a functional SRE that allows DBI/ACBP to be coregulated with other genes involved in lipid metabolism.
Laboratory for Experimental Medicine and Endocrinology, Faculty of Medicine, Onderwijs en Navorsing, Gasthuisberg, Catholic University of Leuven, B-3000 Leuven, Belgium. johan.swinnen@med.kuleuven.ac.be
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Swinnen
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Alen
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Heyns
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Verhoeven
D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins / Q000502:physiology*; D017124:Conserved Sequence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D026261:Diazepam Binding Inhibitor; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D016415:Sequence Alignment; D013256:Steroids / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D026261:Diazepam Binding Inhibitor; D009687:Nuclear Proteins; D012333:RNA, Messenger; C497387:SREBF1 protein, human; C497389:Srebf1 protein, rat; D013256:Steroids; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors