Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription

被引:144
作者
Raspé, E
Duez, H
Mansén, A
Fontaine, C
Fiévet, C
Fruchart, JC
Vennström, B
Staels, B
机构
[1] Inst Pasteur, UR 545, INSERM, F-59019 Lille, France
[2] Grp Merck, Ctr Rech & Dev, F-69003 Lyon, France
[3] Karolinska Inst, Dept Cellular & Mol Biol, S-17177 Stockholm, Sweden
[4] Univ Lille, Fac Pharm, F-59006 Lille, France
关键词
apolipoprotein C-III; triglycerides; nuclear receptors;
D O I
10.1194/jlr.M200386-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Elevated serum levels of triglyceride-rich remnant lipoproteins (TRL) are a major risk factor predisposing a subject to atherosclerosis. Apolipoprotein C-III (apoC-III) is a major constituent of TRL that impedes triglyceride hydrolysis and remnant clearance and, as such, may exert pro-atherogenic activities. In the present study, transient cotransfection experiments in rat hepatocytes in primary culture and rabbit kidney RK13 cells demonstrated that overexpression of Rev-erbalpha specifically decreases basal and HNF-4 stimulated human apoC-III promoter activity. A Rev-erbalpha response element was mapped by promoter deletion, mutation analysis, and gel-shift experiments to a AGGTCA half-site located at position -23/-18 (downstream of the TATA box) in the apoC-III promoter. Finally, Rev-erbalpha-deficient mice displayed elevated serum and liver mRNA levels of apoC-III together with increased serum VLDL triglycerides. Taken together, our data identify Rev-erbalpha as a regulator of apoC-III gene expression, providing a novel, physiological role for this nuclear receptor in the regulation of lipid metabolism.
引用
收藏
页码:2172 / 2179
页数:8
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