Molecular basis of the inverse agonism of 3β-Hydroxy-27- NOR-5-Cholestenoic Acid on LXRβ

M. VIRGINIA DANSEY; LAUTARO D. ALVAREZ; DIEGO Y GRINMAN; DANIELA NAVALESI; RENÉ HOUTMAN; DARIO A ESTRIN; GERARDO BURTON; ADALI PECCI

Bariloche

Simposio; 3rd South American Symposium in Signal Transduction and Molecular Medicine; 2015

IFIBYNE-UBA-CONICET

Liver X receptors LXRα and LXRβ are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. LXRα is highly expressed in liver, small intestine, kidney, spleen and adipose tissue whereas LXRβ was found to be expressed ubiquitously. Once activated, LXRs are involved in a myriad of physiological functions as de novo synthesis of cholesterol, excretion and detoxification of bile acids or lipids, glucose homeostasis, immunity, skin development and homeostasis, neurological functions, cell proliferation and apoptosis. Oxidized cholesterol metabolites, oxysterols, are endogenous LXR activators and the 25R-cholestenoic acid (25R-CA) showed to be a potent LXR activator.Based on these observations we designed a simplified side-chains analogue 27-norcholestenoic acid (L1) witch proved to be an inverse agonist of LXRβ.