NR1H2,3 binds the ABCG5 gene

Stable Identifier
R-HSA-9029521
Type
Reaction [binding]
Species
Homo sapiens
Compartment
Synonyms
LXR binds the ABCG5 gene
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Cell-based and in vivo studies using mice showed that the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8 genes are direct targets of the oxysterol-activated liver X receptor alpha (LXRα or NR1H3) and LXRβ (NR1H2) (Repa JJ et al. 2002; Berge KE et al. 2000). The LXR agonist T0901317 markedly upregulated mRNA levels of Abcg5 and Abcg8 in the small intestine and liver of wild type (WT), but not NR1H3 or NR1H3/H2- knockout mice (Repa JJ et al. 2002; van der Veen et al. 2007). Further, treatment with T0901317 increased fecal neutral sterol excretion from WT, but not Abcg5-/- mice (Plösch T et al. 2006). These data suggest that in the intestine, activation of NR1H2,3 leads to the upregulation of the transmembrane transporters ABCG5 and ABCG8 resulting in decreased intestinal sterol absorption. The human ABCG5 and ABCG8 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. Using a reporter construct, the intergenic region was found to act as a bidirectional promoter (Remaley AT et al. 2002). Through elaborate deletion studies, two LXR response elements (LXRE) were identified in intronic regions of the human ABCG8 gene to confer sterol regulation of ABCG5 and ABCG8 genes (Back SS et al. 2013). Electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays demonstrated the binding of NR1H3 to these LXRE regions in the nuclei of human liver cancer HepG2 cells (Back SS et al. 2013).

In mammalian cells, ABCG5 and ABCG8 form 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 premature cardiovascular disease (Berge KE et al. 2000; Lee MH et al. 2001).

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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