ABCA1 gene transcription regulated by NR1H2 or NR1H3

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R-HSA-9605057
Type
Reaction [omitted]
Species
Homo sapiens
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The ATP-binding cassette transporter A1 (ABCA1) gene is transcribed to yield mRNA.

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).

Literature References
PubMed ID Title Journal Year
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
14764426 Role of p160 coactivator complex in the activation of liver X receptor

Huuskonen, J, Fielding, PE, Fielding, CJ

Arterioscler. Thromb. Vasc. Biol. 2004
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