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学科主题基础医学
Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells - A novel role of SREBP in regulating cholesterol metabolism
Zeng, LF; Liao, HL; Liu, Y; Lee, TS; Zhu, MJ; Wang, X; Stemerman, MB; Zhu, Y; Shyy, JYJ
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
2004-11-19
DOI10.1074/jbc.M407817200
279期:47页:48801-48807
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]DENSITY-LIPOPROTEIN DEFICIENCY ; SHEAR-STRESS ACTIVATION ; TANGIER-DISEASE ; GENE-EXPRESSION ; TRANSCRIPTION FACTOR ; UP-REGULATION ; ABCA1 GENE ; PROMOTER ; EFFLUX ; LIVER
英文摘要

ATP-binding cassette transporter A1 (ABCA1) is a pivotal regulator of cholesterol efflux from cells to apolipoproteins, whereas sterol-responsive element-binding protein 2 (SREBP2) is the key protein regulating cholesterol synthesis and uptake. We investigated the regulation of ABCA1 by SREBP2 in vascular endothelial cells (ECs). Our results showed that sterol depletion activated SREBP2 and increased its target, low density lipoprotein receptor mRNA, with a concurrent decrease in the ABCA1 mRNA. Transient transfection analysis revealed that sterol depletion decreased the ABCA1 promoter activity by 50%, but low density lipoprotein receptor promoter- and the sterol-responsive element-driven luciferase activities were increased. Overexpression of the N terminus of SREBP2 (SREBP2(N)), an active form of SREBP2, also inhibited the ABCA1 promoter activity. Functionally adenovirus-mediated SREBP2(N) expression increased cholesterol accumulation and decreased apoA-I-mediated cholesterol efflux. The conserved E-box motif was responsible for the SREBP2(N)-mediated inhibition since mutation of the E-box increased the basal activity of the ABCA1 promoter and abolished the inhibitory effect of SREBP2(N). Furthermore sterol depletion and SREBP2(N) overexpression induced the binding of SREBP2(N) to both consensus and ABCA1-specific E-box. Chromatin immunoprecipitation assay demonstrated that serum starvation enhanced the association of SREBP2 and the ABCA1 promoter in ECs. To correlate this mechanism pathophysiologically, we found that oscillatory flow caused the activation of SREBP2 and therefore attenuated ABCA1 promoter activity in ECs. Thus, this SREBP-regulated mechanism may control the efflux of cholesterol, which is a newly defined function of SREBP2 in ECs in addition to its role in cholesterol uptake and biosynthesis.

语种英语
WOS记录号WOS:000225098100040
Citation statistics
Cited Times:66[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67805
Collection北京大学基础医学院_生理学与病理生理学系
作者单位1.Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA
2.Peking Univ, Ctr Hlth Sci, Key Lab Mol Cardiovasc Sci Educ Minist, Dept Physiol, Beijing 100083, Peoples R China
Recommended Citation
GB/T 7714
Zeng, LF,Liao, HL,Liu, Y,et al. Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells - A novel role of SREBP in regulating cholesterol metabolism[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2004,279(47):48801-48807.
APA Zeng, LF.,Liao, HL.,Liu, Y.,Lee, TS.,Zhu, MJ.,...&Shyy, JYJ.(2004).Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells - A novel role of SREBP in regulating cholesterol metabolism.JOURNAL OF BIOLOGICAL CHEMISTRY,279(47),48801-48807.
MLA Zeng, LF,et al."Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells - A novel role of SREBP in regulating cholesterol metabolism".JOURNAL OF BIOLOGICAL CHEMISTRY 279.47(2004):48801-48807.
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