Characterization of a cholesterol response element (CRE) in the promoter of the cholesteryl ester transfer protein gene: functional role of the transcription factors SREBP-1a, -2, and YY1

J Lipid Res. 1999 Jul;40(7):1284-93.


Cholesteryl ester transfer protein (CETP) is expressed in human adipocytes, where it acts to promote selective uptake of HDL-CE (Benoist, F., M. McDonnell, P. Lau, R. Milne, and R. McPherson. 1997. J. Biol. Chem. 272: 23572;-23577). In contrast to other major sterol-responsive genes such as 3-hydroxy-3-methylglutaryl coenzyme A reductase CETP expression is up-regulated rather than down-regulated in response to cholesterol. To define elements involved in cholesterol-mediated up-regulation of CETP gene expression, deletion derivatives of the CETP promoter were cloned into a luciferase reporter construct and transfected into the human liposarcoma cell line SW872, cultured in the presence or absence of lipoproteins. A fragment associated with a positive cholesterol response was identified between nucleotides -361 and -138 (relative to the initiation site of transcription) of the promoter. This region contains a tandem repeat of a sequence known to mediate sterol dependent regulation of the hamster HMG-CoA reductase gene. We have putatively denoted this region, the cholesterol response element (CRE). Using gel mobility shift assays we demonstrate that both YY1 and SREBP-1 interact with the CRE of CETP. Furthermore, in transient co-transfection experiments, both YY1 and SREBP-1a were found to trans-activate, in a dose-dependent manner, the luciferase activity of constructs harboring the CRE. We also demonstrate that SREBP-2, is able to trans-activate a luciferase construct harboring the CRE although much less effectively as compared to SREBP-1. Finally, functional analysis of the CRE confirms its regulatory role in modulating CETP gene expression through its interaction with YY1 and SREBP-1a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins*
  • Carrier Proteins / genetics*
  • Cholesterol / metabolism*
  • Cholesterol Ester Transfer Proteins
  • Cricetinae
  • DNA / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Erythroid-Specific DNA-Binding Factors
  • Glycoproteins*
  • Humans
  • Hydroxycholesterols / blood
  • Lipids / blood
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic*
  • RNA, Messenger / metabolism
  • Sequence Analysis, DNA
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Transfection
  • Tumor Cells, Cultured
  • YY1 Transcription Factor
  • Zinc Fingers


  • CCAAT-Enhancer-Binding Proteins
  • CETP protein, human
  • Carrier Proteins
  • Cholesterol Ester Transfer Proteins
  • DNA-Binding Proteins
  • Erythroid-Specific DNA-Binding Factors
  • Glycoproteins
  • Hydroxycholesterols
  • Lipids
  • Nuclear Proteins
  • RNA, Messenger
  • SREBF1 protein, human
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors
  • YY1 Transcription Factor
  • YY1 protein, human
  • 25-hydroxycholesterol
  • DNA
  • Cholesterol