Received for publication May 1, 2008.
Revised September 18, 2008.
Accepted for publication September 24, 2008.

The Selective Alzheimer's Disease Indicator-1 Gene (Seladin-1/DHCR24) is a Liver X Receptor Target Gene

Abstract

The nuclear hormone receptors liver X receptor (LXR) and LXR 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 downregulated in regions of the brain associated with Alzheimer's disease. Seladin-1 has been demonstrated to be neuroprotective and was later characterized as 3-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 LXRE within the second intron of this gene that is able to confer LXR specific ligand responsiveness to reporter gene in both HepG2 and HEK293 cells. Furthermore, we found that Seladin-1/DHCR24 gene expression is significantly decreased in skin isolated from LXR null mice. Our data suggest that Seladin-1/DHCR24 is a LXR target gene and that LXR may regulate lipid raft formation.

Key words: PPARs, Promoter analysis