Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription
Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription
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DOI：
10.1194/jlr.m200386-jlr200
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发表时间：
2002-12-01
影响因子：
6.5
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Raspé, E;Duez, H;Staels, B
富含磷脂酰肌醇的残余脂蛋白（TRL）的血清水平升高是使受试者易患动脉粥样硬化的主要风险因素。载脂蛋白C-III（apoC-III）是TRL的主要成分，其阻碍甘油三酯水解和残余物清除，并且因此可发挥促动脉粥样硬化活性。在本研究中，大鼠肝细胞和兔肾RK 13细胞的瞬时共转染实验表明，过表达Rev-erbalpha特异性降低基础和HNF-4刺激的人apoC-III启动子活性。通过启动子缺失、突变分析和凝胶迁移实验，将Rev-erbalpha应答元件定位到位于apoC-III启动子-23/-18位（TATA盒下游）的AGGTCA半位点。最后，Rev-erbalpha缺陷小鼠血清和肝脏apoC-III mRNA水平升高，血清VLDL甘油三酯升高。总之，我们的数据确定Rev-erbalpha作为apoC-III基因表达的调节剂，提供了一种新的，这种核受体在脂质代谢的调节生理作用。
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.