Abstract
The nuclear hormone receptors liver X receptor α (LXRα) 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-Δ24 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 LXRα target genes, we identified an LXRα 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.
Footnotes
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This work was supported by a grant from the National Institutes of Health to T.P.B. (DK080201).
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ABBREVIATIONS: Seladin-1, Selective Alzheimer's disease indicator-1; LXR, liver X receptor; LXRE, liver X receptor response element; Aβ, amyloid β protein; DHCR24, 3β-hydroxysterol-Δ24 reductase; RXR, retinoid X receptor; PCR, polymerase chain reaction; KO, knockout; WT, wild type; ChIP, chromatin immunoprecipitation; HEK, human embryonic kidney; EMSA, electrophoretic mobility shift assay; LDL, low-density lipoprotein; BACE, β-secretase; AD, Alzheimer's disease; APP, amyloid precursor protein; DRM, detergent-resistant membrane domain; GW3965, 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride; T0901317, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide; 22R OHC, 22R-hydroxycholesterol.
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↵1 Current affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida.
- Received May 1, 2008.
- Accepted September 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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