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 that are involved in regulation of cholesterol transport and metabolism. Expression of cholesterol 7alpha-hydroxylase, cholesteryl ester transfer protein 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 5alpha, 6alpha-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 sulfates, had no antagonistic activity. Using chimeric receptors, the antagonistic activity of ECHS was dependent on its interaction with the ligand-binding domain of LXR. ECHS disrupts recruitment of the co-activator Grip 1 into a complex with agonist-bound LXR and this may be responsible for the observed antagonistic properties of these compounds. In various cultured cells, these LXR antagonists also promote de novo cholesterol synthesis and apoptosis. 7-Ketocholesterol and 5alpha, 6alpha-epoxycholesterol are present in blood and have been found in atherosclerotic plaques. If sulfated forms of these oxidized sterols are also present, they may have an important role in foam cell formation by inhibiting LXR function. Since LXR agonists can counteract the activity of these antagonists, they may have therapeutic potential against atherosclerosis.