Srebp-2 Positively Regulates Transcription of the Cholesterol Efflux Gene, Abca1, by Generating Oxysterol Ligands for Lxr.
From: School of Biotechnology and Biomolecular Sciences, Biosciences Building D26, The University of New South Wales, Sydney, NSW 2052, Australia.
The Biochemical journal
- Publish Date: Dec 2006
- ISSN: 1470-8728
- Volume: 400
- Issue: 3
- Pages: 485-91
- Medium: Internet
- Language: English
- Citation (JAMA): Wong Jenny, Quinn Carmel M, Brown Andrew J, et al. Srebp-2 Positively Regulates Transcription of the Cholesterol Efflux Gene, Abca1, by Generating Oxysterol Ligands for Lxr.. Biochem. J. Dec 2006;400:485-91
Abstract
Cholesterol accumulation and removal are regulated by two different transcription factors. SREBP-2 (sterol-regulatory-element-binding protein-2) is best known to up-regulate genes involved in cholesterol biosynthesis and uptake, whereas LXR (liver X receptor) is best known for up-regulating cholesterol efflux genes. An important cholesterol efflux gene that is regulated by LXR is the ATP-binding cassette transporter, ABCA1 (ATP-binding cassette transporter-A1). We have previously shown that statin treatment down-regulated ABCA1 expression in human macrophages, probably by inhibiting synthesis of the LXR ligand 24(S),25-epoxycholesterol. However, it was subsequently reported that ABCA1 expression is down-regulated by SREBP-2 through binding of SREBP-2 to an E-box element in ABCA1’s proximal promoter. As statin treatment induces SREBP-2 activation, this may provide an alternative explanation for the statin-mediated down-regulation of ABCA1. In the present study, we employed a set of CHO (Chinese-hamster ovary) mutant cell lines to investigate the role of SREBP-2 in the regulation of ABCA1. We observed increased ABCA1 mRNA levels in SREBP-2-overexpressing cells and decreased levels in cells lacking a functional SREBP-2 pathway, which were restored when the SREBP-2 pathway was reinstated. Moreover, ABCA1 gene expression was positively associated with synthesis of 24(S),25-epoxycholesterol in these cell lines. In studies using a human ABCA1 promoter reporter assay, mutation of the E-box motif had a similar response as the wild-type construct to either statin treatment or addition of 24(S),25-epoxycholesterol. By contrast, these responses were completely ablated when the DR4 element to which LXR binds was mutated. These results support the idea that 24(S),25-epoxycholesterol and statin treatment influence ABCA1 transcription via supply of an LXR ligand and not through an SREBP-2/E-box-related mechanism. In addition, our results indicate a critical role of SREBP-2 as a positive regulator of ABCA1 gene expression by enabling the generation of oxysterol ligands for LXR.
Mesh Headings (Keywords): ATP-Binding Cassette Transporters, Animals, Cell Line, Cholesterol, Cricetinae, DNA-Binding Proteins, Gene Expression Regulation, Humans, Ligands, Receptors, Cytoplasmic and Nuclear, Receptors, Steroid, Sterol Regulatory Element Binding Protein 2, Transcription, Genetic, Up-Regulation
Check for Full Text / PubMed Unique Identifier (PMID): 16901265
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