Molecular basis of the inverse agonism of 3b-hydroxy-27-nor-5-cholestenoic acid on LXRb

DANSEY, MARíA V.; ALVAREZ, LAUTARO D.; GRINMAN, DIEGO Y.; NAVALESI, DANIELA; HOUTMAN, RENE; ESTRíN, DARIO A.; BURTON, GERARDO; PECCI, ADALí

San Carlos de Bariloche

Simposio; The Third South American Symposium in Signal Transduction and Molecular Medicine (SISTAM 2015); 2015

Nuclear liver X receptors (LXRs) are transcription factors activated by cholesterol metabolites containing an oxidized side chain. Due to their ability to regulate lipid and glucose metabolism; cholesterol transport, inflammatory response and proliferation, LXRs have become attractive pharmacological targets to control several diseases as atherosclerosis, type II diabetes, Alzheimer and cancer. Based on the fact that (25R)-3â-hydroxy-5-cholestenoic acid has been described as a LXR ligand, we evaluated the interaction of 3â-hydroxy-27-nor-5-cholestenoic acid with LXRâ. Reporter gene assays, gene expression together with molecular dynamics simulations of the ligand-LXR-LBD complex and in vitro binding of the complex to Nuclear Receptor cofactors unveiled an inverse agonist behavior of this steroid, and the capacity of the complex to bind corepressors rather than coactivators. These results provide a new scaffold in the quest for selective LXR modulators.