LIVER X RECEPTOR ANTAGONISM OF A NOVEL CHOLESTENOIC ACID ANALOGUE

DANSEY, M. V.; NAVALESI, D.; GRINMAN, D. Y,; SAMAJA, G. A.; ALVAREZ, L. D.; VELEIRO, A. S.; BURTON, G.; PECCI, A.

Sorrento

Conferencia; EMBO conference on nuclear receptors; 2013

EMBO

Liver X receptors LXRá and LXRâ are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. Although originally discovered as crucial 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 apoptosis. 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. Oxidized cholesterol metabolites, oxysterols, are believed to be endogenous LXR activators and the 25R- 3â-hydroxy-5-cholestenoic acid showed to be a potent LXR activator. Based on these observations, we designed two analogues with simplified side-chains: 27-nor and 27-nor -Ä24 3â-hydroxy-5-cholestenoic acids. Here we report their synthesis and the in vitro biological activity. 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 LXRá or LXRâ. Furthermore, these compounds also inhibited GW3965 mediated expression induction of endogenous Fatty Acid Synthase gene and Sterol Regulatory Element-Binding Protein. Steroidal LXR antagonists are rare, and it has been proposed that LXRá/â dual antagonism may reduce triglyceride levels in hypertriglyceridemic patients without affecting cholesterol homeostasis.