Biochemical and Biophysical Research Communications, Vol.284, No.4, 1065-1070, 2001
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.