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PMID:15358760

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Citation

Zeng, L, Liao, H, Liu, Y, Lee, TS, Zhu, M, Wang, X, Stemerman, MB, Zhu, Y and Shyy, JY (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. J. Biol. Chem. 279:48801-7

Abstract

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.

Links

PubMed Online version:10.1074/jbc.M407817200

Keywords

ATP-Binding Cassette Transporters/metabolism; Adenosine Triphosphate/metabolism; Adenoviridae/genetics; Blotting, Northern; Blotting, Western; Cells, Cultured; Cholesterol/metabolism; Chromatin Immunoprecipitation; DNA-Binding Proteins/metabolism; DNA-Binding Proteins/physiology; Down-Regulation; Endothelium, Vascular/cytology; Endothelium, Vascular/metabolism; Humans; Mutation; Oscillometry; Plasmids/metabolism; Promoter Regions, Genetic; Protein Binding; Protein Structure, Tertiary; RNA, Messenger/metabolism; Receptors, LDL/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sterol Regulatory Element Binding Protein 2; Sterols/metabolism; Time Factors; Transcription Factors/metabolism; Transcription Factors/physiology; Transcription, Genetic; Transfection; Umbilical Veins/cytology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ABCA1

involved_in

GO:0071404: cellular response to low-density lipoprotein particle stimulus

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ABCA1

involved_in

GO:0034616: response to laminar fluid shear stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MYC

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:USF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRBP1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MAX

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRBP2

acts_upstream_of

GO:0010886: positive regulation of cholesterol storage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0000167)

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001158)

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001158)

Seeded From UniProt

complete

HUMAN:SRBP2

acts_upstream_of

GO:0090370: negative regulation of cholesterol efflux

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:USF2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ABCA1

involved_in

GO:0034616: response to laminar fluid shear stress

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ABCA1

involved_in

GO:0071404: cellular response to low-density lipoprotein particle stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:APOA1

involved_in

GO:0033344: cholesterol efflux

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MYC

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0090370: negative regulation of cholesterol efflux

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0072368: regulation of lipid transport by negative regulation of transcription from RNA polymerase II promoter

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0071499: cellular response to laminar fluid shear stress

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0071404: cellular response to low-density lipoprotein particle stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

involved_in

GO:0010886: positive regulation of cholesterol storage

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SRBP2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SRBP2

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

occurs_at:(SO:0001952)

Seeded From UniProt

complete

See also

References

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