Liver X receptor antagonism of a novel cholesteoic acid analogue.

DANSEY, V.; NAVLESI D; GRINMAN, D; SAMAJA GA; ALVAREZ, LD; VELEIRO AS; BURTON, G.; PECCI, A.

Sorrento

Simposio; EMBO Conference Series on Nuclear Receptors: Linking molecules, genomes & physiology; 2013

EMBO

Liver X receptors LXRα and LXRβ are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Although originally discovered as pivotal regulators of cholesterol homeostasis, the known roles of LXRs continue to grow with the study of many cell types and animal models. 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 and cell proliferation and apoptosis1. Considering that alterations in lipid metabolism and development of a chronic inflammatory state are associated to different diseases, LXRs have been proposed as key factors affecting human life span[2]. Oxidized cholesterol metabolites, oxysterols, are believed to be endogenous LXR activators and the 25R-Cholestenoic acid showed to be a potent LXR activator2. Based on these observations, here we report the synthesis and the in vitro biological activity of simplified 27-nor and 27-nor Δ24 analogues of cholestenoic acids. Both compounds showed at 10-5M, antagonistic activity when co-incubated with the LXR agonist GW3965 [10-6M] in cells transfected with a reporter luciferase vector responding to the receptor. Furthermore, these compounds also inhibited GW3965 mediated expression induction of endogenous Fatty Acid Synthase gene and Sterol Regulatory Element-Binding Protein.