A CYP7A promoter binding factor site and Alu repeat in the distal promoter region are implicated in regulation of human CETP gene expression

The cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport in mediating the transfer of cholesteryl ester from HDL to atherogenic apolipoprotein B-containing lipoproteins (VLDL, IDL, and LDL). Variation in plasma CETP mass in both normolipidemic and dyslipidemic individuals may reflect differences in CETP gene expression. As the 5' flanking sequence up to 3.4 kb of the human CETP gene contributes to transcriptional activity and tissue-specific gene expression, we evaluated the role of the distal promoter region in the modulation of CETP gene expression. In transfection experiments in HepG2 cells, we presently demonstrate that an Alu repeat (72,153/-2,414) acts as a repressive element, whereas a binding site for the orphan nuclear receptor CYP7A promoter binding factor (CPF), at position -1,042, facilitates activation of human CETP promoter activity. Cotransfection of liver receptor homolog, the mouse homologue of CPF in HEK293 cells that lack CPF, indicated that the -1,042 CPF site is sufficient to induce CPF-mediated activation of CETP promoter activity. Taken together, our results indicate that the distal-promoter region is a major component in the modulation of human CETP promoter activity, and that it may contribute to the liver-specific expression of the CETP gene.