Cholesterol biosynthesic enzymes and inborn errors

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The present study was undertaken to determine the chromosomal mapping of the human squalene epoxidase gene (SQLE). PCR evidence localizes human SQLE to chromosome 8 by hybrid panel as templete. Since the locus of the Langer-Giedion (LG) syndrome genes (8q24.1), a congenital abnormality, is close to the locus of human SQLE(8q24.1), SQLE is considered the candidate for the LG syndrome gene(s). The human SQLE consisted about 17 kb long and organized into 11 exons and 10 intorns ranging from 87 to 3.2 kb. We characterized a new SREBP-la and a typical NF-Y binding sites in the promoter of the human SE gene. Both sites are functional in the transcriptional levels of SQLE. Transcription of reporter genes of LXR responsive element (LXRE) and human SE promoter were studied with the effects of lipoprotein deficient serum (LPDS) and oxysterols in LXR α-transfected HeLa cells. Compared with LXR α transgene negative cells, LXRE was significantly induced by LPDS in positive cells and 25-hydroxycholesterol reinforced the induction. In contrast, SE was reciprocally suppressed under the same conditions. Transfection of LXR α mutant failed to support LXRE induction and SE suppression. Those induction and supporession were completely dependent on the LXRs overexpression and oxysterol ligands having specific structure. It is suggested that LXRs may involve in cholesterol homeostasis through the action of target gene product(s) of LXRs by suppressing SE, a key synthesizing enzyme of the endogenous oxysterol ligands for LXRs.