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Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana (Y.W., P.M.R., T.P.B.); Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana (K.R.S., C.S., G.V.); and Wyeth Research, Collegeville, Pennsylvania (Q.S., S.N.)
The nuclear hormone receptors liver X receptor
(LXR
) and LXRβ function as physiological receptors for oxidized cholesterol metabolites (oxysterols) and regulate several aspects of cholesterol and lipid metabolism. Seladin-1 was originally identified as a gene whose expression was down-regulated in regions of the brain associated with Alzheimer's disease. Seladin-1 has been demonstrated to be neuroprotective and was later characterized as 3β-hydroxysterol-
24 reductase (DHCR24), a key enzyme in the cholesterologenic pathway. Seladin-1 has also been shown to regulate lipid raft formation. In a whole genome screen for direct LXR
target genes, we identified an LXR
occupancy site within the second intron of the Seladin-1/DHCR24 gene. We characterized a novel LXR response element within the second intron of this gene that is able to confer LXR-specific ligand responsiveness to reporter gene in both HepG2 and human embryonic kidney 293 cells. Furthermore, we found that Seladin-1/DHCR24 gene expression is significantly decreased in skin isolated from LXRβ-null mice. Our data suggest that Seladin-1/DHCR24 is an LXR target gene and that LXR may regulate lipid raft formation.
Received for publication May 1, 2008.
Accepted for publication September 24, 2008.
Address correspondence to: Dr. Thomas P. Burris, The Scripps Research Institute, 5353 Parkside Dr., Jupiter, FL 33458. E-mail: tburris{at}scripps.edu