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

Division of Endocrinology, Diabetes, and Metabolism (C.A.P., J.M.W., D.J.S., S.J., J.T.M., M.A.L.), Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Discovery Medicinal Chemistry (J.L.C., W.J.Z., T.M.W.), GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398; and Cardiovascular and Urology Center of Excellence in Drug Discovery (M.W., M.J.), GlaxoSmithKline, King of Prussia, Pennsylvania 19406

Address all correspondence and requests for reprints to: Mitchell A. Lazar, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. E-mail: lazar{at}mail.med.upenn.edu.

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.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRα  |  RXRα

Coregulators:   SRC-1  |  NCOR

Ligands:   T0901317  |  GW 3965