miR-144 binds to the 3'UTR of the ABCA1 mRNA

Stable Identifier
R-HSA-9657791
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Reaction [binding]
Species
Homo sapiens
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Expression of the ATP-binding cassette transporter A1 (ABCA1) gene is induced by oxysterol-activated transcription factors liver X receptor α (LXRα, NR1H3) and LXRβ (NR1H2) and their heterodimeric partners, retinoid X receptors (RXR) via functional LXR response element (LXRE) (Costet P et al. 2000; 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 HDL particles (Vedhachalam C et a. 2007; Ignatova ID et al. 2013). MicroRNA (miR-144) was found to bind the 3'-untranslated region (3'UTR) of ABCA1 mRNA to prohibit translation and reduce ABCA1-mediated cholesterol efflux from hepatocytes (de Aguiar Vallim TQ et al. 2013). In the liver, the farnesoid X receptor (FXR or NR1H4) often acts in opposition to LXRs in the regulation of cholesterol homeostasis. Indeed, FXR activation increases miR-144 expression to decrease hepatic ABCA1 levels and reduce circulating HDL concentrations in mouse models (de Aguiar Vallim TQ et al. 2013). Further, overexpression of miR-144 in a human hepatoma cell line (Hep3B) resulted in a decrease in both ABCA1 protein and efflux of cholesterol to lipid-poor ApoA-I, in the absence of a change in ABCA1 mRNA (de Aguiar Vallim TQ et al. 2013). Hepatic ABCA1 activity is responsible for ~75% of circulating HDL levels (with adipose and intestine contributing to the remainder). While macrophage ABCA1 activity is important in limiting foam cell formation during atherogenesis, macrophage ABCA1-generated HDL particles are not sufficiently abundant to significantly impact the circulating HDL pool. Of note, FXR is not expressed in macrophages, thus FXR/miR-144 is unlikely to contribute greatly to foam cell formation in atherogenesis, but FXR/miR-144 will more dramatically alter circulating serum HDL concentrations through its actions in the liver (de Aguiar Vallim TQ et al. 2013).

Literature References
PubMed ID Title Journal Year
23519696 MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor

de Aguiar Vallim, TQ, Tarling, EJ, Kim, T, Civelek, M, Baldán, A, Esau, C, Edwards, PA

Circ. Res. 2013
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