Sterol-independent repression of low density lipoprotein receptor promoter by peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha).
10.3858/emm.2009.41.6.046
- Author:
Jae Hoon JEONG
1
;
Sehyung CHO
;
Youngmi KIM PAK
Author Information
1. Age-Related and Brain Diseases Research Center, Department of Nanopharmaceutical and Life Sciences, Department of Physiology, Kyung Hee University College of Medicine, Seoul 130-701, Korea. ykpak@khu.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
cholesterol;
liver;
peroxisome-proliferator-activated receptor-gamma coactivator-1;
PPARgamma;
promoter regions, genetic
- MeSH:
Base Sequence;
Cell Line, Tumor;
Cholesterol/metabolism;
Estrogen Receptor alpha/metabolism;
Gene Expression Regulation;
Heat-Shock Proteins/*genetics/*metabolism;
Humans;
Molecular Sequence Data;
Promoter Regions, Genetic;
RNA, Messenger/genetics;
Receptors, LDL/*genetics/*metabolism;
Sterol Regulatory Element Binding Protein 2/metabolism;
Transcription Factors/*genetics/*metabolism;
p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
- From:Experimental & Molecular Medicine
2009;41(6):406-416
- CountryRepublic of Korea
- Language:English
-
Abstract:
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.