title: Cytochrome P450 27A1 Deficiency and Regional Differences in Brain Sterol Metabolism Cause Preferential Cholestanol Accumulation in the Cerebellum.
abstract: Cytochrome P450 27A1 (CYP27A1 or sterol 27-hydroxylase) is a ubiquitous, multifunctional enzyme catalyzing regio- and stereospecific hydroxylation of different sterols. In humans, complete CYP27A1 deficiency leads to cerebrotendinous xanthomatosis or nodule formation in tendons and brain (preferentially in the cerebellum) rich in cholesterol and cholestanol, the 5α-saturated analog of cholesterol. InCyp27a1-/-mice, xanthomas are not formed, despite a significant cholestanol increase in the brain and cerebellum. The mechanism behind cholestanol production has been clarified, yet little is known about its metabolism, except that CYP27A1 might metabolize cholestanol. It also is unclear why CYP27A1 deficiency results in preferential cholestanol accumulation in the cerebellum. We hypothesized that cholestanol might be metabolized by CYP46A1, the principal cholesterol 24-hydroxylase in the brain. We quantified sterols along with CYP27A1 and CYP46A1 in mouse models (Cyp27a1-/-,Cyp46a1-/-,Cyp27a1-/-Cyp46a1-/-, and two wild type strains) and human brain specimens.In vitroexperiments with purified P450s were conducted as well. We demonstrate that CYP46A1 is involved in cholestanol removal from the brain and that several factors contribute to the preferential increase in cholestanol in the cerebellum arising from CYP27A1 deficiency. These factors include (i) low cerebellar abundance of CYP46A1 and high cerebellar abundance of CYP27A1, the lack of which probably selectively increases the cerebellar cholestanol production; (ii) spatial separation in the cerebellum of cholesterol/cholestanol-metabolizing P450s from a pool of metabolically available cholestanol; and (iii) weak cerebellar regulation of cholesterol biosynthesis. We identified a new physiological role of CYP46A1, an important brain enzyme and cytochrome P450 that could be activated pharmacologically.
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and.
authors.forename: Natalia
authors.initials: N
authors.lastname: Mast
authors.affiliation: the Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899.|the Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, and.
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Anderson
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Lin
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: the Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899.|the Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, and.
authors.forename: Illarion V
authors.initials: IV
authors.lastname: Turko
authors.affiliation: Neurology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Curtis
authors.initials: C
authors.lastname: Tatsuoka
authors.affiliation: the Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, 141 86 Huddinge, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Bjorkhem
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences and iap8@case.edu.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Pikuleva
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D004083:Cholestanol / Q000378:metabolism*; D002783:Cholestenones / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D002783:Cholestenones; C002656:7 alpha-hydroxy-4-cholesten-3-one; D004083:Cholestanol; D002784:Cholesterol; D000072556:Cholesterol 24-Hydroxylase; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse
keywords: brain; cerebellum; cholesterol; cholesterol metabolism; cholesterol regulation; cytochrome P450