Selective Partial Agonism of Liver X Receptor alpha Is Related to Differential Corepressor Recruitment

Phelan CA, Weaver JM, Steger DJ, Joshi S, Maslany JT, Collins JL, Zuercher WJ, Willson TM, Walker M, Jaye M, Lazar MA
Source: Mol Endocrinol
Publication Date: (2008)
Issue: epub: online
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Hep G2
Species: human
Tissue Origin: liver
Nucleofector® I/II/2b
Classically, activated transcription by nuclear receptors (NRs) is due to a ligand-induced switch from corepressor to coactivator bound states. However, coactivators and corepressors recognize overlapping surfaces of liganded and unliganded NRs, respectively. Here we show that, at sufficiently high concentration, the NR Corepressor (NCoR) influences the activity of the liver X receptor (LXR) even in the presence of a potent full agonist that destabilizes NCoR binding. Partial agonist ligands that less effectively dissociate NCoR from LXR are even more sensitive to NCoR levels, in a target-gene selective manner. Thus, differential recruitment of NCoR is a major determinant of partial agonism and selective LXR modulation of target genes.