Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism

The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRalpha (hLXRalpha) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2-4 h. Analysis of the hLXRalpha promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRalpha:RXR and LXRbeta:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRalpha:RXR (type 11 LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRa and LXRbeta activity, whereas the type 11 LXRE acts as a weaker and selective mediator of LXRalpha activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRalpha gene expression. This would lead to increased hLXRalpha levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.