Cloning of the human cholesteryl ester hydrolase promoter: Identification of functional peroxisomal proliferator-activated receptor responsive elements

Cholesteryl ester hydrolase (CEH) is responsible for hydrolysis of stored cholesterol esters in macrophage foam cells and release of free cholesterol for high-density lipoprotein-mediated efflux. PCR-based screening of human genomic libraries with human macrophage CEH specific primers resulted in amplification and cloning of 1.7 kb promoter sequence. Analysis of the sequence revealed a lack of consensus TATA-box but presence of a GC-rich proximal sequence, a CAAT box and several binding sites for the transcription factor Spl. Three putative response elements for peroxisome proliferator-activated receptor (PPRE) were identified at position -176, -779, and -1.316. Downregulation of promoter activity was observed in the presence of either PPAR alpha- or PPAR gamma -specific ligands and introduction of a 4-point transverse mutation in the PPRE at -176 completely abolished the effect of PPAR ligands on the promoter activity. Analogous to other genes involved in macrophage cholesterol homeostasis, human CEH may also be regulated by PPAR. (C) 2001 Academic Press.