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Journal of Lipid Research, Vol. 44, 1322-1331, July 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Regulation of human CETP gene expression

Wilfried Le Goff, Maryse Guerin, Laure Petit, M. John Chapman¹ and Joëlle Thillet

Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 551 <<Dyslipoproteinemias and Atherosclerosis: Genetics, Metabolism and Therapy>>, Hôpital de la Pitié, 83 boulevard de l'Hôpital 75651 Paris, France

¹ To whom correspondence should be addressed. e-mail: chapman{at}chups.jussieu.fr

Cholesteryl ester transfer protein (CETP) is a key factor in plasma reverse cholesterol transport and is implicated in the pathophysiology of atherogenic dyslipidemia. Variations observed in plasma CETP mass and activity in both normolipidemic and dyslipidemic individuals may reflect differences in CETP gene expression. We evaluated the respective roles of the Sp1 and Sp3 transcription factors on the promoter activity of the human CETP gene at a new Sp1/Sp3 site identified at position -690, and at two previously described Sp1/Sp3 sites at positions -37 and -629. In transient transfection in HepG2 cells, site-directed mutagenesis using luciferase reporter constructs containing a promoter fragment from +32 to -745 indicated that the new -690 site acts as a repressive element in reducing CETP promoter activity (-22%; P < 0.05); equally, this site exerts an additive effect with the -629 site, inducing marked repression (-42%; P < 0.005). In contrast, in NCTC cells that display a 16-fold lower level of Sp3, the repressive effect at the -690 site was enhanced 2-fold (-45%; P < 0.05), whereas the -629 site exerted no effect. Cotransfection of Sp1 and/or Sp3 in SL2 insect cells lacking endogenous Sp factors demonstrated that Sp1 and Sp3 act as activators at the -690 and -37 sites, whereas Sp3 acts as a repressor at the -629 site.

Taken together, our data demonstrate that Sp1 and Sp3 regulate human CETP promoter activity through three Sp1/Sp3 binding sites in a distinct manner, and that the Sp1/Sp3 ratio is a key factor in determining the relative contribution of these sites to total promoter activity.

Supplementary key words reverse cholesterol transport • atherosclerosis • transcriptional repression

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