Oxysterol binds to the ABCA1 gene:NR1H2,3:RXR:NCOR:GPS2:TBL1:HDAC3 complex

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R-HSA-9024326
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Reaction [binding]
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Homo sapiens
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In macrophages, excess of cholesterol leads to the formation of oxysterols, the natural ligands of liver X receptors LXRα (NR1H3) and LXRβ (NR1H2), which belong to the nuclear receptor superfamily of ligand-activated transcription factors. Activation of NR1H2,3 induces expression of ATP-binding cassette transporter A1 (ABCA1), which acts in the plasma membrane and endosomal system to promote cellular cholesterol transfer to lipid-poor apolipoproteins, such as ApoA1 and ApoE associated with high density lipoprotein (HDL) formation (Ignatova ID et al. 2013; Vedhachalam C et a. 2007). NR1H3 (LXRα) was found to be a stronger activator of ABCA1 expression in response to LXR agonists in mouse bone marrow-derived macrophages and in human primary macrophages (Bischoff ED et al. 2010; Ishibashi M et al. 2013). Cholesteryl esters accumulate in various tissues of mice lacking NR1H3, and in cells of the male reproductive system this is directly attributable to reduced expression of ABCA1 (Ouvrier A et al. 2009). Moreover, loss of ABCA1 in humans results in Tangier disease, a condition in which patients have extremely low levels of circulating HDL, massive accumulation of cholesterol in macrophages, and an increased risk for developing atherosclerosis (Rust S et al. 1999). Treatment with the synthetic NR1H2,3 agonist, T0901317, increased expression of ABCA1 mRNA in cells and tissues of wild type, but not NR1H2,3-null mice (Wagner BL et al. 2003; Repa JJ et al. 2000). At the same time, “unliganded” NR1H2,3 repressed basal expression of ABCA1 in a tissue-specific manner, occurring in macrophages and intestinal mucosa but not in several other mouse tissues (Wagner BL et al. 2003). Treatment of human THP-1 macrophages with endogenous (25-hydroxycholesterol) or synthetic (T0901317) NR1H2,3 ligands stimulated both transcriptional and posttranscriptional pathways affecting ABCA1 expression (Ignatova ID et al. 2013).

NR1H2 or NR1H3 heterodimerizes with retinoid X receptors (RXR) and binds to LXR-response elements (LXREs) consisting of a direct repeat of the core sequence 5'-AGGTCA-3' separated by 4 nucleotides (DR4) in the DNA of target genes (Wiebel FF & Gustafsson JA 1997). The human ABCA1 promoter was found to contain a LXRE located about 50 bp upstream of the transcription start site (Costet P et al. 2000). Gel shift experiments showed that NR1H2,3:RXR heterodimers bind to the isolated LXREs from human ABCA1 (Costet P et al. 2000). Further, the ligand-selective regulation of ABCA1 was observed when ABCA1 promoter-luciferase reporter constructs were transfected into human embryonic kidney 293T cells or human liver carcinoma HepG2 cells that were then treated with T0901317 or 25-hydroxycholesterol to show enhanced luciferase activity (Ignatova ID et al. 2013). Unliganded LXR:RXR actively suppresses transcription by recruiting a corepressor complex. A mammalian two-hybrid analysis, using GAL4 fusions of the receptor interaction domains (ID) from the nuclear receptor corepressor (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT or NCOR2) transiently co-expressed with VP-16 fusions of NR1H3 or NR1H2 ligand binding domains in monkey kidney fibroblasts CV-1 cells showed that in the absence of ligand, both NR1H2 and NR1H3 interacted with the corepressor IDs of NCOR and SMRT (Wagner BL et al. 2003). Biochemical work has identified a core complex consisting of NCOR, histone deacetylase 3 (HDAC3), transducin β-like proteins (TBL1, TBLR1), and G protein pathway suppressor 2 (GPS2) (Zhang J et al. 2002). The chromatin immunoprecipitation (ChIP) assays in HepG2 cells revealed that, in the absence of GW3965, a synthetic NR1H2,3 agonist, NCOR and HDAC3 were associated with ABCA1 promoter, while agonist treatment caused their dissociation and induced recruitment of histone acetyltransferase (HAT) CBP and RNA polymerase II (Jakobsson T et al. 2009). TBLR1 was also present at the promoter and unaffected by the ligand status. GPS2 was found to occupy the ABCA1 promoter in the absence of ligand but was released upon GW3965 treatment, while NR1H2,3 (LXR) recruitment was observed already in the absence of ligand and further enhanced upon ligand activation (Jakobsson T et al. 2009). The inclusion of RXR in the re-ChIP assays demonstrates that GPS2 associates with the LXR:RXR heterodimer. Importantly, similar recruitment patterns were obtained in human THP-1 macrophages. Thus, at the ABCA1 promoter, NR1H2,3 ligand triggers exchange of a GPS corepressor complex (containing NCoR, HDAC3, TBLR1) for the coactivator complex devoid of GPS2 (Jakobsson T et al. 2009).

Literature References
PubMed ID Title Journal Year
10858438 Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor

Costet, P, Luo, Y, Wang, N, Tall, AR

J. Biol. Chem. 2000
19481530 GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus

Jakobsson, T, Venteclef, N, Toresson, G, Damdimopoulos, AE, Ehrlund, A, Lou, X, Sanyal, S, Steffensen, KR, Gustafsson, JA, Treuter, E

Mol. Cell 2009
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