RT Journal Article
SR Electronic
T1 Identification of 5α,6α-epoxycholesterol as a Novel Modulator of LXR Activity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.065193
DO 10.1124/mol.110.065193
A1 Thomas J. Berrodin
A1 Qi Shen
A1 Elaine M. Quinet
A1 Matthew R. Yudt
A1 Leonard P. Freedman
A1 Sunil Nagpal
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/09/13/mol.110.065193.abstract
AB The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily that function as key transcriptional regulators of a number of biological processes including cholesterol homeostasis, lipid metabolism and keratinocyte differentiation. Natural ligands that activate LXRs include oxysterol derivatives such as 25-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, 20(S)-hydroxychoelsterol and 24(S),25-epoxycholesterol. Related oxysterols, such as 5α,6α-epoxycholesterol (5,6-EC) are present in a number of foods and have been shown to induce atherosclerosis in animal models. Intriguingly, these oxysterols have also been detected in atherosclerotic plaques. Using a variety of biochemical and cellular assays, we demonstrate that 5,6-EC is the first dietary modulator and an endogenous LXR ligand with cell- and gene-context dependent antagonist, agonist and inverse agonist activities. In a multiplexed LXR-cofactor peptide interaction assay, 5,6-EC induced the recruitment of a number of cofactor peptides onto both LXRα and LXRβ, and showed an EC50 of approximately 2μM in peptide recruitment. Further, 5,6-EC bound to LXRα in a radiolabeled ligand displacement assay (EC50 = 76 nM), thus demonstrating it to be one of the most potent natural LXRα ligands known to date. Analysis of endogenous gene expression in various cell-based systems indicated the potential of 5,6-EC to antagonize LXR-mediated gene expression. Furthermore, it also induced the expression of some LXR-responsive genes in keratinocytes. These results clearly demonstrate that 5,6-EC is an LXR modulator that may play a role in the development of lipid disorders, such as atherosclerosis by antagonizing the agonistic action of endogenous LXR ligands.