Research Article: Cross-Talk between Oxysterols and Glucocorticoids: Differential Regulation of Secreted Phopholipase A2 and Impact on Oligodendrocyte Death

Date Published: November 26, 2009

Publisher: Public Library of Science

Author(s): Amalia Trousson, Joelle Makoukji, Patrice X. Petit, Sophie Bernard, Christian Slomianny, Michael Schumacher, Charbel Massaad, Colin Combs. http://doi.org/10.1371/journal.pone.0008080

Abstract: Oxysterols are oxidized forms of cholesterol. They have been shown to be implicated in cholesterol turnover, inflammation and in neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis. Glial cells are targets of oxysterols: they inhibit astrocyte proliferation after brain injury, and we have previously shown that 25-hydroxycholesterol (25OH) provokes oligodendrocyte apoptosis and stimulates the expression of sPLA2 type IIA (sPLA2-IIA), which has a protective effect.

Partial Text: Cholesterol is predominantly located in the brain, especially in the myelin sheaths formed by oligodendrocytes [1], which are the myelinating glial cells of the central nervous system. It also exerts pleiotropic effects on brain functioning and homeostasis and gives rise to several neuroactive compounds, mainly side-chain cleavage-derived steroid hormones and oxysterols. The latter are natural compounds originating from the enzymatic oxidation of cholesterol. There are several different oxysterols, in particular 24(S)-hydroxycholesterol (24(S)-OH), 25-hydroxycholesterol (25-OH) and 27-hydroxycholesterol (27-OH), which are respectively synthesized by means of the cholesterol hydroxylase enzymes CYP46A1, 25-hydroxylase and 27-hydroxylase [2]. Oxysterols have been shown to be implicated in cholesterol turnover, inflammation and in neurodegenerative diseases such as Alzheimer’s disease (AD) [3], [4] and multiple sclerosis (MS) [5], [6]. Not only neurons, but also glial cells are targets for the actions of oxysterols: they inhibit astrocyte proliferation after brain injury [7] and, as we have previously shown, can cause oligodendrocyte apoptosis [8].

Oxysterols are important molecules for brain homeostasis, and their levels are altered in several neurodegenerative disease like AD and demyelinating diseases (MS, Smith-Lemli-Optiz disease) [5], [6], [28]. Our previous data showed that oxysterols, and in particular 25-OH, can provoke oligodendrocyte apoptosis, but also stimulate the synthesis of the sPLA2-IIA with partial protective effects [8]. In this study, we have analyzed the effects of the glucocorticoid Dex (often used as anti-inflammatory agent) on oxysterol-induced apoptosis and sPLA2-IIA induction. We have demonstrated that Dex blocks sPLA2-IIA stimulation by oxysterols, an effect which is mediated by the GR. As a matter of fact, GR silencing causes an increase in sPLA2-IIA basal activity as well as its induction by oxysterols. Moreover, it abolishes Dex inhibitory effects towards sPLA2-IIA. Dex negative effects on 25-OH are restricted to sPLA2-IIA because they did not affect the expression of the cholesterol transporter (ABCA1), another 25-OH target gene (not shown).

Source:

http://doi.org/10.1371/journal.pone.0008080

 

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