miR-33 binds to the 3'UTR of the ABCA1 mRNA

Stable Identifier
Reaction [binding]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

ATP-binding cassette transporter A1 (ABCA1) is a target of micro RNA 33 (miR-33) (Rayner KJ et al. 2010; Marquart TJ et al. 2010; Najafi-Shoushtari SH et al.2010; Horie T et al. 2010; Zaiou M et al. 2018). The miR33 family consists of two intronic miRNAs, miR-33a and miR-33b, which are encoded within the introns of the sterol regulatory element-binding proteins (SREBP) 2 and 1 genes, respectively (Marquart TJ et al. 2010; Najafi-Shoushtari SH et al.2010; Horie T et al. 2010). Under conditions that stimulate SREBP transcription, miR-33a/b are co-expressed with their host genes and reciprocally regulate genes such as ABCA1 that are involved in cellular cholesterol efflux and high-density lipoprotein (HDL) biogenesis (Marquart TJ et al. 2010; Najafi-Shoushtari SH et al.2010; Horie T et al. 2010). Expression of the 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) in target genes (Costet P et al. 2000; Ignatova ID et al. 2013). miR-33 was found to suppress expression of ABCA1 in human macrophages (THP-1) and hepatocytes (HepG2, Hep3B ) treated with a synthetic agonist, T0901317, of LXRs (Rayner KJ et al. 2010; Marquart TJ et al. 2010). Inhibition of endogenous miR-33 by anti-miR-33 increased the expression of ABCA1 in THP-1 and HepG2 cells (Rayner KJ et al. 2010). In vivo studies showed that liver ABCA1 protein and serum HDL-C levels were higher in miR-33-deficient mice than in control mice (Horie T et al. 2010). In line with this, a study reported that healthy individuals with high HDL-C levels often overexpress ABCA1 and ABCG1 and show a decrease of miR-33a in their peripheral blood mononuclear cells (Scherrer DZ et al. 2015). Analysis of the 3' untranslated region (3'UTR) of ABCA1 identified sequences that are partially complementary to miR-33 sequences (Marquart TJ et al. 2010). Importantly, these sequences are evolutionarily conserved across animal species (Marquart TJ et al. 2010). Further, a 3'UTR luciferase reporter assay showed that miR-33 directly binds the ABCA1 3′UTR when human embryonic kidney (HEK293T) cells were cotransfected with luciferase reporter constructs fused to the 3′UTR of ABCA1 and control miR or miR-33 (Rayner KJ et al. 2010; Horie T et al. 2010; Najafi-Shoushtari SH et al. 2010). Mutation in the potential binding site in the 3′-UTR abolished the effect of miR-33 (Horie T et al. 2010). The Reactome event describes the miR-33- regulated translation of ABCA1 mRNA in response to NR1H2,3 natural ligands. The annotation is based on studies with T0901317, the synthetic agonist of NR1H2,3 (Rayner KJ et al. 2010; Marquart TJ et al. 2010).

Literature References
PubMed ID Title Journal Year
20566875 miR-33 links SREBP-2 induction to repression of sterol transporters

Marquart, TJ, Allen, RM, Ory, DS, Baldán, A

Proc. Natl. Acad. Sci. U.S.A. 2010
29772548 Epigenetic regulation of genes involved in the reverse cholesterol transport through interaction with miRNAs

Zaiou, M, Rihn, BH, Bakillah, A

Front Biosci (Landmark Ed) 2018
20466882 MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis

Najafi-Shoushtari, SH, Kristo, F, Li, Y, Shioda, T, Cohen, DE, Gerszten, RE, Näär, AM

Science 2010
20466885 MiR-33 contributes to the regulation of cholesterol homeostasis

Rayner, KJ, Suárez, Y, Dávalos, A, Parathath, S, Fitzgerald, ML, Tamehiro, N, Fisher, EA, Moore, KJ, Fernández-Hernando, C

Science 2010
20855588 MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo

Horie, T, Ono, K, Horiguchi, M, Nishi, H, Nakamura, T, Nagao, K, Kinoshita, M, Kuwabara, Y, Marusawa, H, Iwanaga, Y, Hasegawa, K, Yokode, M, Kimura, T, Kita, T

Proc. Natl. Acad. Sci. U.S.A. 2010
Participant Of
Cite Us!