Peroxisome proliferator-activated receptor alpha ligands activate transcription of lectin-like oxidized low density lipoprotein receptor-1 gene through GC box motif.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a receptor for oxidized LDL. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating transcription of various genes. We examined effects of PPAR ligands on LOX-1 expression and their transcriptional regulation in vascular endothelial cells. PPARalpha-specific ligands, such as fenofibrate and WY-14643, but not PPARgamma-specific ligands induced LOX-1 expression. Reduced expression of PPARalpha by antisense oligonucleotides directed to PPARalpha blocked fenofibrate-induced LOX-1 expression. Luciferase reporter gene assays with deletion and point mutations in the LOX-1 promoter revealed that transcriptional activity of LOX-1 gene by fenofibrate was localized in the -114/-106 GC box. Electrophoretic mobility shift assays with the radiolabeled GC box sequence showed inducible bands by PPARalpha ligands, which is competitively suppressed by unlabeled GC box motif and by an antibody to PPARalpha. In conclusion, PPARalpha appears to be one of the key regulators that induce LOX-1 expression, utilizing the GC box as a promoter.
Hayashida
Kazutaka
K
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
Kume
Noriaki
N
Minami
Manabu
M
Inui-Hayashida
Atsuko
A
Mukai
Eri
E
Toyohara
Masako
M
Kita
Toru
T
D000818:Animals; D001482:Base Composition / Q000235:genetics; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D008024:Ligands; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D015533:Transcriptional Activation / Q000502:physiology*
D008024:Ligands; D008077:Lipoproteins, LDL; D047492:Peroxisome Proliferator-Activated Receptors; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein