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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cerebellum / cytology
  • Cerebellum / drug effects
  • Cerebellum / physiology*
  • Cholesterol / metabolism
  • Gene Expression Regulation / drug effects
  • Homeostasis
  • Hydrocarbons, Fluorinated / pharmacology
  • Hydroxycholesterols / pharmacology
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Knockout
  • Myelin Sheath / drug effects
  • Myelin Sheath / genetics
  • Myelin Sheath / physiology*
  • Oligodendroglia / cytology
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism
  • Organ Culture Techniques
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / deficiency
  • Orphan Nuclear Receptors / physiology*
  • Promoter Regions, Genetic
  • Psychomotor Performance / drug effects
  • Psychomotor Performance / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Spatial Learning / drug effects
  • Spatial Learning / physiology
  • Sulfonamides / pharmacology

Substances

  • Hydrocarbons, Fluorinated
  • Hydroxycholesterols
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • RNA, Messenger
  • Sulfonamides
  • TO-901317
  • 25-hydroxycholesterol
  • Cholesterol