Published online before print October 14, 2004, doi: 10.1161/01.ATV.0000147896.69299.85
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© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Transcription Factor Sterol Regulatory Element Binding Protein 2 Regulates Scavenger Receptor Cla-1 Gene Expression
From the National Institute for Health and Medical Research (INSERM), Dyslipoproteinemia and Atherosclerosis Research Unit, Hôpital de la Pitié, Paris Cedex 13, France.
Correspondence to Thierry Huby, INSERM, Unit 551, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83 Boulevard de la Pitié, 75651 Paris Cedex 13. 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.
The putative regulation of the expression of the human scavenger receptor Cla-1 gene by intracellular cholesterol content and SREBP transcription factors was evaluated. Transient transfection, site-directed mutation, and electrophoretic mobility shift assay allowed identification of a functional SRE in the Cla-1 promoter. SREBP-stably transfected cells provided strong evidence of the implication of SREBP-2 in Cla-1 gene expression.
Key Words: SR-BI • SREBP • cholesterol homeostasis • regulation of gene expression • transcription factor
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