Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis

Liver X receptors (LXRs) are members of the nuclear receptor superfamily th at are involved in regulation of cholesterol transport and metabolism. Expr ession of cholesterol 7 alpha -hydroxylase, cholesteryl ester transfer prot ein and certain ATP-binding cassette transporters that are responsible for cholesterol efflux from cells is regulated by LXR and its ligands. In this report we show that 5 alpha, 6 alpha -epoxycholesterol-3-sulfate (ECHS) and 7-ketocholesterol-3-sulfate inhibit transactivation of a reporter gene by LXR. Non-sulfated forms of these compounds, as well as many other steroid s ulfates, had no antagonistic activity. Using chimeric receptors, the antago nistic activity of ECHS was dependent on its interaction with the ligand-bi nding domain of LXR. ECHS disrupts recruitment of the co-activator Grip I i nto a complex with agonist-bound LXR and this may be responsible for the ob served antagonistic properties of these compounds. In various cultured cell s, these LXR antagonists also promote de novo cholesterol synthesis and apo ptosis. 7-Ketocholesterol and 5 alpha, 6 alpha -epoxycholesterol are presen t in brood and have been found ill atherosclerotic plaques. If sulfated for ms of these oxidized sterols are also present, they may have an important r ole in foam cell formation by inhibiting L,YR function. Since LXR a,agonist s can counteract the activity of these antagonists, they may have therapeut ic potential against atherosclerosis. (C) 2001 Elsevier Science Inc. All ri ghts reserved.