title: On the regulatory role of side-chain hydroxylated oxysterols in the brain. Lessons from CYP27A1 transgenic and Cyp27a1(-/-) mice.
abstract: The two oxysterols, 27-hydroxycholesterol (27OH) and 24S-hydroxycholesterol (24OH), are both inhibitors of cholesterol synthesis and activators of the liver X receptor (LXR) in vitro. Their role as physiological regulators under in vivo conditions is controversial, however. In the present work, we utilized a previously described mouse model with overexpressed human sterol 27-hydroxylase (CYP27A1). The levels of 27OH were increased about 12-fold in the brain. The brain levels of HMG-CoA reductase mRNA and HMG-CoA synthase mRNA levels were increased. In accordance with increased cholesterol synthesis, most of the cholesterol precursors were also increased. The level of 24OH, the dominating oxysterol in the brain, was decreased by about 25%, most probably due to increased metabolism by CYP27A1. The LXR target genes were unaffected or slightly changed in a direction opposite to that expected for LXR activation. In the brain of Cyp27(-/-) mice, cholesterol synthesis was slightly increased, with increased levels of cholesterol precursors but normal mRNA levels of HMG-CoA reductase and HMG-CoA synthase. The mRNA levels corresponding to LXR target genes were not affected. The results are consistent with the possibility that both 24OH and 27OH are physiological suppressors of cholesterol synthesis in the brain. The results do not support the contention that 27OH is a general activator of LXR target genes in this organ.
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Sweden.
authors.forename: Zeina
authors.initials: Z
authors.lastname: Ali
authors.forename: Maura
authors.initials: M
authors.lastname: Heverin
authors.forename: Maria
authors.initials: M
authors.lastname: Olin
authors.forename: Jure
authors.initials: J
authors.lastname: Acimovic
authors.forename: Anita
authors.initials: A
authors.lastname: Lövgren-Sandblom
authors.forename: Marjan
authors.initials: M
authors.lastname: Shafaati
authors.forename: Ann
authors.initials: A
authors.lastname: Båvner
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.forename: Eran
authors.initials: E
authors.lastname: Leitersdorf
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
mesh_terms: D000818:Animals; D001921:Brain; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000378:metabolism
chemical_list: D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C044563:24-hydroxycholesterol; C076996:27-hydroxycholesterol; D002784:Cholesterol; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse; D006904:Hydroxymethylglutaryl-CoA Synthase