title: Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum.
abstract: The identification of new pathways governing myelination provides innovative avenues for remyelination. Liver X receptors (LXRs) α and β are nuclear receptors activated by oxysterols that originated from the oxidation of cholesterol. They are crucial for cholesterol homeostasis, a major lipid constituent of myelin sheaths that are formed by oligodendrocytes. However, the role of LXRs in myelin generation and maintenance is poorly understood. Here, we show that LXRs are involved in myelination and remyelination processes. LXRs and their ligands are present in oligodendrocytes. We found that mice invalidated for LXRs exhibit altered motor coordination and spatial learning, thinner myelin sheaths, and reduced myelin gene expression. Conversely, activation of LXRs by either 25-hydroxycholesterol or synthetic TO901317 stimulates myelin gene expression at the promoter, mRNA, and protein levels, directly implicating LXRα/β in the transcriptional control of myelin gene expression. Interestingly, activation of LXRs also promotes oligodendroglial cell maturation and remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Together, our findings represent a conceptual advance in the transcriptional control of myelin gene expression and strongly support a new role of LXRs as positive modulators in central (re)myelination processes.
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France;
authors.forename: Delphine
authors.initials: D
authors.lastname: Meffre
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France;
authors.forename: Ghjuvan'Ghjacumu
authors.initials: G
authors.lastname: Shackleford
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France;
authors.forename: Mehdi
authors.initials: M
authors.lastname: Hichor
authors.affiliation: U-1130 INSERM, CNRS 8246, and Pierre and Marie Curie University, 75005 Paris, France;
authors.forename: Victor
authors.initials: V
authors.lastname: Gorgievski
authors.affiliation: U-1130 INSERM, CNRS 8246, and Pierre and Marie Curie University, 75005 Paris, France;
authors.forename: Eleni T
authors.initials: ET
authors.lastname: Tzavara
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France; UMR-6547, CNRS, and Blaise Pascal University, and Centre de Recherche en Nutrition Humaine d'Auvergne, 63177 Aubière, France;
authors.forename: Amalia
authors.initials: A
authors.lastname: Trousson
authors.affiliation: UMR-788, INSERM, and Paris-Sud University, 94276 Le Kremlin-Bicêtre Cedex, France;
authors.forename: Abdel M
authors.initials: AM
authors.lastname: Ghoumari
authors.affiliation: U-1127 INSERM, Institut du Cerveau et de la Moelle Epinière, Université Pierre et Marie Curie, Paris Sorbonne Universités UMR-S1127, CNRS UMR 7225, 75013 Paris, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Deboux
authors.affiliation: U-1127 INSERM, Institut du Cerveau et de la Moelle Epinière, Université Pierre et Marie Curie, Paris Sorbonne Universités UMR-S1127, CNRS UMR 7225, 75013 Paris, France.
authors.forename: Brahim
authors.initials: B
authors.lastname: Nait Oumesmar
authors.affiliation: UMR-788, INSERM, and Paris-Sud University, 94276 Le Kremlin-Bicêtre Cedex, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Liere
authors.affiliation: UMR-788, INSERM, and Paris-Sud University, 94276 Le Kremlin-Bicêtre Cedex, France;
authors.forename: Michael
authors.initials: M
authors.lastname: Schumacher
authors.affiliation: UMR-788, INSERM, and Paris-Sud University, 94276 Le Kremlin-Bicêtre Cedex, France; charbel.massaad@parisdescartes.fr etienne.baulieu@inserm.fr.
authors.forename: Etienne-Emile
authors.initials: EE
authors.lastname: Baulieu
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charbonnier
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France;
authors.forename: Julien
authors.initials: J
authors.lastname: Grenier
authors.affiliation: UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France; charbel.massaad@parisdescartes.fr etienne.baulieu@inserm.fr.
authors.forename: Charbel
authors.initials: C
authors.lastname: Massaad
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D013449:Sulfonamides; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C007997:25-hydroxycholesterol
keywords: LXR alpha and beta; cerebellum; myelination; oligodendrocytes; oxysterols