Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein

Abstract

The murine Abcg1 gene is reported to consist of 15 exons that encode a single mRNA (herein referred to as Abcg1-a) and protein. We now demonstrate that (i) the murine gene contains two additional coding exons downstream of exon 1, (ii) transcription involves the use of multiple promoters, and (iii) the RNA undergoes alternative splicing reactions. As a result, three mRNAs are expressed that encode three putative protein isoforms that differ at their amino terminus. ABCG1 transcripts are induced in vivo in multiple tissues in response to the liver X receptor ligand T0901317. Identification and characterization of four liver X receptor response elements in the intron downstream of exon 2 provides a mechanism by which this induction occurs. Importantly, cholesterol efflux to high density lipoprotein was stimulated following transfection of Hek293 cells with plasmids encoding individual ABCG1 isoforms. In situ hybridization studies in embryonic day 11.5-15.5 mouse embryos revealed strong expression of ABCG1 transcripts in the olfactory epithelium, hind brain, eye, and dorsal root ganglia. The relatively high levels of expression in neuronal tissues and the eye suggest that ABCG1-dependent cholesterol efflux may be critical for normal neuronal function in addition to its role in macrophages.There are more than 373 members in the ATP-binding cassette (ABC)

ROS and NF-κB but not LXR mediate IL-1β signaling for the downregulation of ATP-binding cassette transporter A1

“…Second, the level of ABCA1 but not ABCG1 mRNA was decreased with IL-1␤ treatment. If LXR is involved, the regulatory pattern of ABCA1 and ABCG1 should be similar (24). Finally, the deletion of the DR4 element from the promoter of ABCA1 did not reverse the effect of IL-1␤.…”

Telmisartan Enhances Cholesterol Efflux from THP-1 Macrophages by Activating PPARγ

“…On the other hand, Laffitte et al 31) reported that LXR agonist-induced ABCA1 and ABCG1 expressions in macrophages were completely abolished by the deletion of both LXR and LXR . Other studies have shown that the ABCG1 gene is transcriptionally activated by activated LXR through its binding elements 12) . Taken together, the above observations suggest that ABCG1 is regulated via PPAR , both in an LXRdependent and -independent manner, and the LXRindependent effect of PPAR activation on ABCG1 expression could overwhelm the inhibitory effect of LXR knockdown on ABCG1.…”

“…LXR and/or PPAR reportedly up-regulated the ATP binding cassette transporters (ABC) A1 9,11) , and ABCG1 12,13) and scavenger receptor class B type (SR-B ) 14) , all of which facilitate cellular cholesterol efflux 12,[15][16][17][18] . The deletion of PPAR 9,19) , LXR 20) , ABCA1 21) , ABCG1 22) , and SR-B 23) in macrophages reportedly accelerates the development of atherosclerosis and treatment with LXR 24) and PPAR 25) ligands inhibits its development; however, it is still not clear whether PPAR -activating ARBs affect the expression of these genes and cholesterol efflux from macrophages, and regulate PPARinducible genes in human cells 26) .…”

High-density lipoproteins: an emerging target in the prevention of cardiovascular disease

“…Patients with Tangier's disease, a syndrome characterised by low plasma levels of HDL-C and impaired cholesterol efflux, are deficient in ABCA1 [22]. It has recently been reported that other ATP-binding proteins, ABCG1 and ABCG5 [23,24], are involved in the efflux of cholesterol to lipidated HDL particles. Immense interest has been focused on the development of pharmacologic strategies that promote the expression of these transmembrane proteins and thus facilitate reverse cholesterol transport.…”