Sterol-independent repression of low density lipoprotein receptor promoter by peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha).

Peroxisome proliferator activated receptor (PPAR) gamma coactivator-1alpha (PGC-1alpha) may be implicated in cholesterol metabolism since PGC-1alpha co-activates estrogen receptor alpha (ERalpha) transactivity and estrogen/ERalpha induces the transcription of LDL receptor (LDLR). Here, we show that overexpression of PGC-1alpha in HepG2 cells represses the gene expression of LDLR and does not affect the ERalpha-induced LDLR expression. PGC-1alpha suppressed the LDLR promoter-luciferase (pLR1563- luc) activity regardless of cholesterol or functional sterol-regulatory element-1. Serial deletions of the LDLR promoter revealed that the inhibition by PGC-1alpha required the LDLR promoter regions between -650 bp and -974 bp. Phosphorylation of PGC-1alpha may not affect the suppression of LDLR expression because treatment of SB202190, a p38 MAP kinase inhibitor, did not reverse the LDLR down-regulation by PGC-1alpha. This may be the first report showing the repressive function of PGC-1alpha on gene expression. PGC-1alpha might be a novel modulator of LDLR gene expression in a sterol-independent manner, and implicated in atherogenesis.