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New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE , two key control enzymes in cholesterol synthesis

Howe, Vicky, Sharpe, Laura J., Prabhu, Anika V., Brown, Andrew J.·2017·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
DOI 10.1016/j.bbalip.2017.03.009
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Abstract

Background The two control points of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and squalene monooxygenase (SQLE) are known targets of the transcription factor sterol-regulatory element binding protein-2 (SREBP-2). Yet the location of the sterol-regulatory elements (SREs) and cofactor binding sites, nuclear factor-Y (NF-Y) and specificity protein 1 (Sp1), have not been satisfactorily mapped in the human SQLE promoter, or at all in the human HMGCR promoter. Methods We used luciferase reporter assays to screen the sterol-responsiveness of a library of predicted SRE, Sp1 and NF-Y site mutants and hence identify bone fide binding sites. We confirmed SREs via an electrophoretic mobility shift assay (EMSA) and ChIP-PCR. Results We identified two SREs in close proximity in both the human HMGCR and SQLE promoters, as well as one NF-Y site in HMGCR and two in SQLE. In addition, we found that HMGCR expression is highly activated only when SREBP-2 levels are very high, in contrast to the low density lipoprotein receptor (LDLR), a result reflected in mouse models used in other studies. Conclusions Both HMGCR and SQLE promoters have two SREs that may act as a homing region to attract a single SREBP-2 homodimer, with HMGCR being activated only when there is absolute need for cholesterol synthesis. This ensures preferential uptake of exogenous cholesterol via LDLR, thereby conserving energy. General significance We provide the first comprehensive investig…

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Metadata

Authors
Howe, V., Sharpe, L. J., Prabhu, A. V., & Brown, A. J.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher
Elsevier BV
Published
2017-07
Volume
1862
Issue
7
Pages
647-657
ISSN
1388-1981
DOI
10.1016/j.bbalip.2017.03.009
Cited by
76
References
0
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Funders
  • National Health and Medical Research Council (1060515)
  • Australian Research Council (DP170101178)
  • University of New South Wales Early Career Research Grant

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