title: 7-Dehydrocholesterol metabolites produced by sterol 27-hydroxylase (CYP27A1) modulate liver X receptor activity.
abstract: 7-Dehydrocholesterol (7-DHC) is a common precursor of vitamin D3 and cholesterol. Although various oxysterols, oxygenated cholesterol derivatives, have been implicated in cellular signaling pathways, 7-DHC metabolism and potential functions of its metabolites remain poorly understood. We examined 7-DHC metabolism by various P450 enzymes and detected three metabolites produced by sterol 27-hydroxylase (CYP27A1) using high-performance liquid chromatography. Two were further identified as 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC. These 7-DHC metabolites were detected in serum of a patient with Smith-Lemli-Opitz syndrome. Luciferase reporter assays showed that 25-hydroxy-7-DHC activates liver X receptor (LXR) α, LXRβ and vitamin D receptor and that 26/27-hydroxy-7-DHC induces activation of LXRα and LXRβ, although the activities of both compounds on LXRs were weak. In a mammalian two-hybrid assay, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC induced interaction between LXRα and a coactivator fragment less efficiently than a natural LXR agonist, 22(R)-hydroxycholesterol. These 7-DHC metabolites did not oppose agonist-induced LXR activation and interacted directly to LXRα in a manner distinct from a potent agonist. These findings indicate that the 7-DHC metabolites are partial LXR activators. Interestingly, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC suppressed mRNA expression of sterol regulatory element-binding protein 1c, an LXR target gene, in HepG2 cells and HaCaT cells, while they weakly increased mRNA levels of ATP-binding cassette transporter A1, another LXR target, in HaCaT cells. Thus, 7-DHC is catabolized by CYP27A1 to metabolites that act as selective LXR modulators.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Endo-Umeda
authors.affiliation: Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki 300-0395, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.affiliation: Department of Nutrition and Health, Faculty of Human Development, Soai University, Suminoe-ku, Osaka 559-0033, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Ohta
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan. Electronic address: makishima.makoto@nihon-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism*; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D003684:Dehydrocholesterols / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000187:drug effects* / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000187:drug effects
chemical_list: C587260:26-hydroxy-7-dehydrocholesterol; D003684:Dehydrocholesterols; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018167:Receptors, Calcitriol; D002784:Cholesterol; C587259:25-hydroxy-7-dehydrocholesterol; C016705:7-dehydrocholesterol; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase
keywords: 1,25(OH)(2)D(3); 1α,25-dihydroxyvitamin D(3); 25-hydroxyvitamin D 1α-hydroxylase; 3β-hydroxysterol-Δ(7)-reductase; 7-DHC; 7-Dehydrocholesterol; 7-dehydrocholesterol; ABCA1; ATP-binding cassette transporter A1; CYP27A1; CYP27B1; DHCR7; GST; HPLC; LXR; Liver X receptor; SLOS; SREBP; Smith–Lemli–Opitz syndrome; Transcription; Vitamin D receptor; glutathione S-transferase; high-performance liquid chromatography; liver X receptor; siRNA; small interfering RNA; sterol 27-hydroxylase; sterol regulatory element-binding protein