on October 14, 2004
Published online before print October 14, 2004, doi: 10.1161/01.ATV.0000147896.69299.85
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Submitted on June 8, 2004
Accepted on September 8, 2004
Transcription Factor Sterol Regulatory Element-Binding Protein 2 Regulates Scavenger Receptor Cla-1 Gene Expression
Morgan Tréguier ;
From the National Institute for Health and Medical Research (INSERM), Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris Cedex 13, France.
* To whom correspondence should be addressed. E-mail: thuby{at}infobiogen.fr.
Objective--The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested that Cla-1 gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whether Cla-1 is a target gene of the sterol regulatory element-binding protein (SREBP) transcription factor family.
Methods and Results--Transient transfections demonstrated that SREBP factors induce Cla-1 promoter activity and that SREBP-2 is a more potent inducer than the SREBP-1a isoform. The 5'-deletion analysis of 3 kb of the 5'-flanking sequence of the Cla-1 gene, combined with site-directed mutagenesis and electrophoretic mobility shift assay, allowed identification of a unique sterol responsive element. SREBP-mediated Cla-1 regulation was confirmed in stably transfected human embryonic kidney 293 cells expressing the active form of SREBP-2 at incremental levels. In these cell lines, Cla-1 mRNA and protein levels were increased in direct proportion to the level of SREBP-2 expression.
Conclusions--These findings provide evidence that SREBP-2, a key regulator of cellular cholesterol uptake through modulation of the expression of the low-density lipoprotein receptor gene, may influence cellular cholesterol homeostasis via regulation of Cla-1 gene expression.
Key words: SR-BI • SREBP • cholesterol homeostasis • regulation of gene expression • transcription factor
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