title: Vitamin D Metabolite, 25-Hydroxyvitamin D, Regulates Lipid Metabolism by Inducing Degradation of SREBP/SCAP.
abstract: Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control lipid homeostasis. SREBP activation is regulated by a negative feedback loop in which sterols bind to SREBP cleavage-activating protein (SCAP), an escort protein essential for SREBP activation, or to insulin-induced genes (Insigs) (endoplasmic reticulum [ER] anchor proteins), sequestering the SREBP-SCAP-Insig complex in the ER. We screened a chemical library of endogenous molecules and identified 25-hydroxyvitamin D (25OHD) as an inhibitor of SREBP activation. Unlike sterols and other SREBP inhibitors, 25OHD impairs SREBP activation by inducing proteolytic processing and ubiquitin-mediated degradation of SCAP, thereby decreasing SREBP levels independently of the vitamin D receptor. Vitamin D supplementation has been proposed to reduce the risk of metabolic diseases, but the mechanisms are unknown. The present results suggest a previously unrecognized molecular mechanism of vitamin D-mediated lipid control that might be useful in the treatment of metabolic diseases.
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan; Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Lisa
authors.initials: L
authors.lastname: Asano
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan; Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Ryoden
authors.affiliation: Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Usuda
authors.affiliation: Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Bilon
authors.initials: B
authors.lastname: Khambu
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Takashima
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Sato
authors.affiliation: Division of Metabolic Medicine, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.affiliation: Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan; CREST, AMED. Electronic address: knaga@cc.tuat.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Uji, Kyoto 611-0011, Japan; Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan; CREST, AMED. Electronic address: uesugi@scl.kyoto-u.ac.jp.
authors.forename: Motonari
authors.initials: M
authors.lastname: Uesugi
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008968:Molecular Conformation; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D014807:Vitamin D; C104450:25-hydroxyvitamin D
keywords: SREBP; Vitamin D