title: 27-Hydroxylation of 7- and 8-dehydrocholesterol in Smith-Lemli-Opitz syndrome: a novel metabolic pathway.
abstract: Smith-Lemli-Opitz syndrome (SLOS) is attributable to mutations in the gene coding for 7-dehydrocholesterol reductase. Low to absent enzyme activity accounts for the accumulation of both 7-dehydrocholesterol and 8-dehydrocholesterol in plasma and other tissues. Since oxysterols can participate in the regulation of cholesterol homeostasis, we examined the possibility that they are formed from these dehydrocholesterol intermediates. In patients with SLOS, we found serum levels of 27-hydroxy-7-dehydrocholesterol ranging from 0.1 to 0.25micro M and evidence for circulating levels of 27-hydroxy-8-dehydrocholesterol (0.04-0.51 micro M). Picomolar quantities of 27-hydroxy-7-dehydrocholesterol were identified in normal individuals. Biologic activities of 27-hydroxy-7-dehydrocholesterol were found to include inhibition of sterol synthesis and the activation of nuclear receptor LXRalpha but not that of LXRbeta. These activities occurred at concentrations found in plasma and presumably at those existing in tissues. Thus, patients with SLOS have increased levels of metabolites derived from intermediates in cholesterol synthesis that are biologically active and may contribute to the regulation of cholesterol synthesis in vivo.
authors.affiliation: National Institute of Child Health and Human Development, National Institute of Health Bethesda, Maryland, MD 20892, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Jisong
authors.initials: J
authors.lastname: Cui
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Norman B
authors.initials: NB
authors.lastname: Javitt
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002775:Cholestadienols / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D003684:Dehydrocholesterols / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D006900:Hydroxylation; D007223:Infant; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019082:Smith-Lemli-Opitz Syndrome / Q000097:blood / Q000378:metabolism*
chemical_list: D002775:Cholestadienols; D004268:DNA-Binding Proteins; D003684:Dehydrocholesterols; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C076996:27-hydroxycholesterol; C026359:cholesta-5,8-dien-3 beta-ol; D002784:Cholesterol; C016705:7-dehydrocholesterol