ACTIVATION OF THE NUCLEAR RECEPTOR LXR BY OXYSTEROLS DEFINES A NEW HORMONE RESPONSE PATHWAY

Accumulation of cholesterol causes both repression of genes controllin g cholesterol biosynthesis and cellular uptake and induction of choles terol 7 alpha-hydroxylase, which leads to the removal of cholesterol b y increased metabolism to bile acids, Here, we report that LXR alpha a nd LXR beta, two orphan members of the nuclear receptor superfamily, a re activated by 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7 alph a-hydroxylase gene, Our data provide evidence for a new hormonal signa ling pathway that activates transcription in response to oxysterols an d suggest that LXRs play a critical role in the regulation of choleste rol homeostasis.