Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.
Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7alpha-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXRalpha and LXRbeta, two orphan members of the nuclear receptor superfamily, are 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 7alpha-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis.
Lehmann
J M
JM
Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. jml30414@glaxo.com
Kliewer
S A
SA
Moore
L B
LB
Smith-Oliver
T A
TA
Oliver
B B
BB
Su
J L
JL
Sundseth
S S
SS
Winegar
D A
DA
Blanchard
D E
DE
Spencer
T A
TA
Willson
T M
TM
D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D006888:Hydroxycholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C044563:24-hydroxycholesterol; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase