Endocrine Abstracts

Oxysterols are reactive molecules generated from the oxidation of cholesterol. Few data are available about their functions in myelination of nervous system. Our aim was to study the influence of oxysterols on myelin gene expression and myelin sheath formation by oligodendrocytes (central nervous system), and by Schwann cells (peripheral nervous system). We show by gas chromatography/mass spectrometry that oligodendrocytes and Schwann cells contain 24(S)-hydroxycholesterol, 25-hydroxycholesterol and 27-hydroxycholesterol, and that they express their biosynthetic enzymes and receptors (liver X receptors: LXRα and LXRβ). We demonstrate that oxysterols activate the expression of central myelin genes (PLP and MBP) in oligodendrocytes, but inhibit peripheral myelin genes expression (MPZ, PMP22) in a Schwann cells.

In the CNS, we showed that the activating effects of oxysterols were restricted to the cerebellum and dependant of LXR presence as myelin gene expression was drastically reduced in this structure in LXR-KO mice. By, using organotypic cultures of cerebellum slices, we showed that oxysterols were able to stimulate myelin gene expression after lysolecithin-induced demyelination and enhance remyelination process.

In the PNS, the down-regulation of myelin genes is mediated either by LXRα or LXRβ, depending on the promoter context. Importantly, the knockout of LXR in mice results in thinner myelin sheaths surrounding the axons of the nerves. Oxysterols repress peripheral myelin genes via two mechanisms: by binding of LXRs to myelin gene promoters and by inhibiting the Wnt/beta-catenin pathway that is crucial for the expression of myelin genes.

Altogether our results reveal new mechanisms of action of oxysterols and open new perspectives for the treatment of demyelinating diseases by targeting LXR.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.