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G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2, NR1H3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009).
G-protein pathway suppressor 2 (GPS2) was identified as a co-regulator required for NR1H2,3-induced transcription of the ABCG1 gene in human hepatic HepG2 and macrophage THP-1 cells (Jakobsson T et al. 2009). In macrophages, silencing of GPS2 by RNA interference reduced ABCG1 expression and diminished ABCG1-mediated cholesterol efflux. Chromatin immunoprecipitation analysis and 2-hybrid and protein-protein interaction assays revealed that GPS2 interacted with NR1H2,3:RXR heterodimer at the LXRE of the ABCG1 promoter (Jakobsson T et al. 2009). Chromosome conformation capture assays using the human hepatoma cell line, Huh7, transfected with GPS2-targeting siRNAs showed that GPS2 was required for intrachromosomal communication of the ABCG1 promoter and enhancer triggered by NR1H2,3 activation (Jakobsson T et al. 2009). Further, ligand activation of NR1H2,3 induced two functionally coupled GPS2-dependent processes: (1) receptor recruitment to an ABCG1 promoter/enhancer unit and (2) lysine-specific histone demethylase 1 (KDM1)-dependent H3K9 demethylation (Jakobsson T et al. 2009). The model suggests that the H3K9 methylation imposes a chromatin barrier at certain genomic loci (e.g., ABCG1) that prevents nuclear receptors (NR) (e.g., NR1H2,3) from high-affinity DNA binding (as detected by ChIP assays). Ligand activation in vivo triggers recruitment of KDMs to NRs (in the case of NR1H2,3 via GPS2), thereby facilitating H3K9 demethylation and high-affinity DNA binding (Jakobsson T et al. 2009).
T0901317 or GW3965, two synthetic agonists of liver X-receptors (LXRα, NR1H3 and LXRβ, NR1H2) or cholesterol-loading significantly induced the expression of ABCA1 mRNA in mouse RAW 264.7 and human THP1 macrophage cell lines (Costet P et al. 2000; Venkateswaran A et al. 2000; Whitney KD et al. 2001; Jakobsson T et al. 2009). Similar regulation of ABCA1 mRNA expression by NR1H2, 3 agonists was observed in human peripheral blood-derived monocytes (Larrede S et al. 2009). Treatment with T0901317 increased expression of ABCA1 mRNA in variety of cells and tissues isolated from wild type but not LXR-/- mice (lacking both NR1H3 and NR1H2) (Repa JJ et al. 2000; Wagner BL et al. 2003). At the same time, 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) ligands of NR1H2,3 stimulated both transcriptional and posttranscriptional events to enhance ABCA1 expression (Ignatova ID et al. 2013). NR1H2,3-induced expression of ABCA1 is thought to promote ABCA1-mediated cellular cholesterol transport across the plasma membrane to lipid-poor apolipoproteins, such as ApoA1 and ApoE in the generation of nascent high-density lipoproteins (HDL) particles (Ignatova ID et al. 2013; Vedhachalam C et a. 2007). 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).
Multiple microRNAs have been identified as regulators of ABCA1 mRNA levels (Horie T et al. 2010; Sun D et al. 2012; de Aguiar Vallim TQ et al. 2013).
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