Expression of ABCG8 regulated by NR1H2 or NR1H3

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R-HSA-9029591
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Reaction [omitted]
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Homo sapiens
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The ATP-binding cassette sub-family G member 8 (ABCG8) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. In mammalian cells, ABCG8 and ABCG5 form obligate heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion (Berge KE et al. 2000; Graf GA et al. 2002, 2003; reviewed by Yu XH et al. 2014). Consistent with these functions, ABCG5 and ABCG8 are expressed almost exclusively on the brush border membranes of enterocytes and in the canalicular membranes of hepatocytes (Yu XH et al. 2014). ABCG5 and ABCG8 mutations are responsible for sitosterolemia, a genetic disorder in which patients accumulate cholesterol and plant sterols in the circulation and are at increased risk for developing premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001). In the pathogenesis of cholesterol gallstone disease, the upregulation of ABCG5 and ABCG8 in gallstone patients, possibly mediated by increased NR1H3 (LXRα), may contribute to the cholesterol supersaturation of bile (Jiang ZY et al. 2008). As shown in mice, both Abcg8 and Abcg5 are target genes of the liver X receptor α (LXRα, NR1H3) and can be induced by LXRs agonists (Repa JJ et al. 2002; Yu L et al. 2003). The human ABCG8 and ABCG5 genes, each with 13 exons, are located next to each other in a head-to-head configuration on chromosome 2p21 (Remaley AT et al. 2002). Their start codons are separated by a 374-bp intergenic region, which is highly conserved among several species (Remaley AT et al. 2002). The luciferase reporter assay in human liver carcinoma HepG2 cells revealed that the intergenic region of ABCG5 and ABCG8 genes acted as a bidirectional promoter, and contained binding sites for hepatocyte nuclear factor 4α (HNF4α), liver receptor homolog 1 (LRH1) and GATA transcription factors (Remaley AT et al. 2002; Sumi K et al. 2007; Freeman LA et al. 2004). Further, electrophoretic mobility shift (EMSA), chromatin immunoprecipitation (ChIP) (ChIP), and cell reporter assays demonstrated the binding of NR1H3 to two intronic regions of the human ABCG8 gene to confer LXR-mediated regulation of ABCG5 and ABCG8 genes in HepG2 cells (Back SS et al. 2013). Finally, co-expression of the pABCG8-LUC reporter plasmid with an appropriate combination of the expression plasmids of five transcription factors, NR1H3 (LXRα), RXRα, GATA4, HNF4α, and LRH-1 in the HepG2 cells showed synergistic transcriptional activation of ABCG8 gene (Back SS et al. 2013).

Literature References
PubMed ID Title Journal Year
23790976 Cooperative transcriptional activation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 genes by nuclear receptors including Liver-X-Receptor

Back, SS, Kim, J, Choi, D, Lee, ES, Choi, SY, Han, K

BMB Rep 2013
12150943 Comparative genome analysis of potential regulatory elements in the ABCG5-ABCG8 gene cluster

Remaley, AT, Bark, S, Walts, AD, Freeman, L, Shulenin, S, Annilo, T, Elgin, E, Rhodes, HE, Joyce, C, Dean, M, Santamarina-Fojo, S, Brewer, HB

Biochem. Biophys. Res. Commun. 2002
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