Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins.
3β-Hydroxysterol Δ24-reductase (DHCR24) catalyzes a final step in cholesterol synthesis, and has been ascribed diverse functions, such as being anti-apoptotic and anti-inflammatory. How this enzyme is regulated transcriptionally by sterols is currently unclear. Some studies have suggested that its expression is regulated by Sterol Regulatory Element Binding Proteins (SREBPs) while another suggests it is through the Liver X Receptor (LXR). However, these transcription factors have opposing effects on cellular sterol levels, so it is likely that one predominates. Here we establish that sterol regulation of DHCR24 occurs predominantly through SREBP-2, and identify the particular region of the DHCR24 promoter to which SREBP-2 binds. We demonstrate that sterol regulation is mediated by two sterol regulatory elements (SREs) in the promoter of the gene, assisted by two nearby NF-Y binding sites. Moreover, we present evidence that the dual SREs work cooperatively to regulate DHCR24 expression by comparison to two known SREBP target genes, the LDL receptor with one SRE, and farnesyl-diphosphate farnesyltransferase 1, with two SREs.
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia.
Eser J
EJ
Zerenturk
Laura J
LJ
Sharpe
Andrew J
AJ
Brown
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D023081:CCAAT-Binding Factor / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D008055:Lipids / Q000096:biosynthesis*; D000071518:Liver X Receptors; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D057093:Orphan Nuclear Receptors / Q000502:physiology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology*; D013261:Sterols / Q000494:pharmacology*
D023081:CCAAT-Binding Factor; D008055:Lipids; D000071518:Liver X Receptors; D009419:Nerve Tissue Proteins; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; D013186:Farnesyl-Diphosphate Farnesyltransferase