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Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7587-92. doi: 10.1073/pnas.1424951112. Epub 2015 May 28.

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum.

Author information

1
UMR-S 1124 INSERM, Paris Descartes University, Sorbonne Paris Cité University, Centre Interdisciplinaire Chimie Biologie-Paris (FR 3567, CNRS), 75270 Paris Cedex 6, France;
2
U-1130 INSERM, CNRS 8246, and Pierre and Marie Curie University, 75005 Paris, France;
3
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;
4
UMR-788, INSERM, and Paris-Sud University, 94276 Le Kremlin-Bicêtre Cedex, France;
5
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.
6
UMR-788, INSERM, and Paris-Sud University, 94276 Le Kremlin-Bicêtre Cedex, France; charbel.massaad@parisdescartes.fr etienne.baulieu@inserm.fr.
7
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.

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.

KEYWORDS:

LXR alpha and beta; cerebellum; myelination; oligodendrocytes; oxysterols

PMID:
26023184
PMCID:
PMC4475952
DOI:
10.1073/pnas.1424951112
[Indexed for MEDLINE]
Free PMC Article

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