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SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1, by generating oxysterol ligands for LXR

Wong, Jenny, Quinn, Carmel M., Brown, Andrew J.·2006·Biochemical Journal
DOI 10.1042/bj20060914
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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.

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Research works printed but not linked: 33

  1. Goldstein, 2006, Protein sensors for membrane sterols, Cell, 124, 35, 10.1016/j.cell.2005.12.022 · DOI · Paper page
  2. Briggs, 1993, Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence, J. Biol. Chem., 268, 14490, 10.1016/S0021-9258(19)85265-1 · DOI · Paper page
  3. Kim, 1995, Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix–loop–helix domain, Mol. Cell. Biol., 15, 2582, 10.1128/MCB.15.5.2582 · DOI
  4. Costet, 2000, Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor, J. Biol. Chem., 275, 28240, 10.1074/jbc.M003337200 · DOI
  5. Edwards, 2002, LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis, Vasc. Pharmacol., 38, 249, 10.1016/S1537-1891(02)00175-1 · DOI
  6. Tall, 2000, Tangier disease as a test of the reverse cholesterol transport hypothesis, J. Clin. Invest., 106, 1205, 10.1172/JCI11538 · DOI
  7. Soumian, 2005, ABCA1 and atherosclerosis, Vasc. Med., 10, 109, 10.1191/1358863x05vm593ra · DOI
  8. Willy, 1995, LXR, a nuclear receptor that defines a distinct retinoid response pathway, Genes Dev., 9, 1033, 10.1101/gad.9.9.1033 · DOI
  9. Peet, 1998, The LXRs: a new class of oxysterol receptors, Curr. Opin. Genet. Dev., 8, 571, 10.1016/S0959-437X(98)80013-0 · DOI
  10. Venkateswaran, 2000, Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα, Proc. Natl. Acad. Sci. U.S.A., 97, 12097, 10.1073/pnas.200367697 · DOI · Paper page
  11. Teboul, 1995, OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor, Proc. Natl. Acad. Sci. U.S.A., 92, 2096, 10.1073/pnas.92.6.2096 · DOI
  12. DeBose-Boyd, 2001, Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands, Proc. Natl. Acad. Sci. U.S.A., 98, 1477, 10.1073/pnas.98.4.1477 · DOI · Paper page
  13. Janowski, 2001, The hypocholesterolemic agent LY295427 reverses suppression of sterol regulatory element-binding protein processing mediated by oxysterols, J. Biol. Chem., 276, 45408, 10.1074/jbc.M108348200 · DOI
  14. Bjorkhem, 2002, Do oxysterols control cholesterol homeostasis?, J. Clin. Invest., 110, 725, 10.1172/JCI0216388 · DOI
  15. Schroepfer, 2000, Oxysterols: modulators of cholesterol metabolism and other processes, Physiol. Rev., 80, 361, 10.1152/physrev.2000.80.1.361 · DOI
  16. Spencer, 1985, 24(S),25-Epoxycholesterol. Evidence consistent with a role in the regulation of hepatic cholesterogenesis, J. Biol. Chem., 260, 13391, 10.1016/S0021-9258(17)38732-X · DOI
  17. Wong, 2004, Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux, Arterioscler. Thromb. Vasc. Biol., 24, 2365, 10.1161/01.ATV.0000148707.93054.7d · DOI
  18. Zeng, 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, 10.1074/jbc.M407817200 · DOI
  19. Brown, 2002, Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism, Mol. Cell, 10, 237, 10.1016/S1097-2765(02)00591-9 · DOI · Paper page
  20. Goldstein, 1983, Receptor-mediated endocytosis of low-density lipoprotein in cultured cells, Methods Enzymol., 98, 241, 10.1016/0076-6879(83)98152-1 · DOI
  21. Nohturfft, 1998, Sterols regulate processing of carbohydrate chains of wild-type SREBP cleavage-activating protein (SCAP), but not sterol-resistant mutants Y298C or D443N, Proc. Natl. Acad. Sci. U.S.A., 95, 12848, 10.1073/pnas.95.22.12848 · DOI
  22. Metherall, 1989, Loss of transcriptional repression of three sterol-regulated genes in mutant hamster cells, J. Biol. Chem., 264, 15634, 10.1016/S0021-9258(19)84879-2 · DOI
  23. Rawson, 1999, Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein, J. Biol. Chem., 274, 28549, 10.1074/jbc.274.40.28549 · DOI · Paper page
  24. Janowski, 1999, Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ, Proc. Natl. Acad. Sci. U.S.A., 96, 266, 10.1073/pnas.96.1.266 · DOI
  25. Yang, 1994, Sterol-resistant transcription in CHO cells caused by gene rearrangement that truncates SREBP-2, Genes Dev., 8, 1910, 10.1101/gad.8.16.1910 · DOI
  26. Hasan, 1994, Somatic cell genetic and biochemical characterization of cell lines resulting from human genomic DNA transfections of Chinese hamster ovary cell mutants defective in sterol-dependent activation of sterol synthesis and LDL receptor expression, Somat. Cell Mol. Genet., 20, 183, 10.1007/BF02254759 · DOI
  27. Rawson, 1997, Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs, Mol. Cell, 1, 47, 10.1016/S1097-2765(00)80006-4 · DOI · Paper page
  28. Langmann, 2002, Identification of sterol-independent regulatory elements in the human ATP-binding cassette transporter A1 promoter: role of Sp1/3, E-box binding factors, and an oncostatin M-responsive element, J. Biol. Chem., 277, 14443, 10.1074/jbc.M110270200 · DOI
  29. Yang, 2002, The E-box motif in the proximal ABCA1 promoter mediates transcriptional repression of the ABCA1 gene, J. Lipid Res., 43, 297, 10.1016/S0022-2275(20)30172-3 · DOI
  30. Forman, 1997, The orphan nuclear receptor LXRα is positively and negatively regulated by distinct products of mevalonate metabolism, Proc. Natl. Acad. Sci. U.S.A., 94, 10588, 10.1073/pnas.94.20.10588 · DOI
  31. Fu, 2001, 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells, J. Biol. Chem., 276, 38378, 10.1074/jbc.M105805200 · DOI
  32. Lund, 2003, Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis, Arterioscler. Thromb. Vasc. Biol., 23, 1169, 10.1161/01.ATV.0000056743.42348.59 · DOI
  33. Field, 2004, Stanol esters decrease plasma cholesterol independently of intestinal ABC sterol transporters and Niemann–Pick C1-like 1 protein gene expression, J. Lipid Res., 45, 2252, 10.1194/jlr.M400208-JLR200 · DOI

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Metadata

Authors
Wong, J., Quinn, C. M., & Brown, A. J.
Affiliations
  • School of Biotechnology and Biomolecular Sciences, Biosciences Building D26, The University of New South Wales, Sydney, NSW 2052, Australia
  • Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2006-11-28
Volume
400
Issue
3
Pages
485-491
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20060914
Cited by
127
References
0
Language
en

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