Selective partial agonism of liver X receptor alpha is related to differential corepressor recruitment.
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.
Phelan
Caroline A
CA
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, USA.
Weaver
Joseph M
JM
Steger
David J
DJ
Joshi
Shree
S
Maslany
Jeffrey T
JT
Collins
Jon L
JL
Zuercher
William J
WJ
Willson
Timothy M
TM
Walker
Max
M
Jaye
Michael
M
Lazar
Mitchell A
MA
D001565:Benzoates / Q000737:chemistry / Q000378:metabolism; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D057093:Orphan Nuclear Receptors; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D001565:Benzoates; D001596:Benzylamines; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D013449:Sulfonamides; C473027:GW 3965; C539127:NCOR1 protein, human; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides