For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
Inviting an author to review:
Radio-wave detection of ultra-high-energy neutrinos and cosmic rays
Find an author and click ‘Invite to review selected article’ near their name.
Search for authorsSearch for similar articles
26
views
35
references
 Top references
cited by
9
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      332
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          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.

          Methodology/Principal Findings

          As glucocorticoids are well-known for their anti-inflammatory effects, our aim was to understand their direct effects on oxysterol-induced responses in oligodendrocytes (sPLA2-IIA stimulation and apoptosis). We demonstrate that the synthetic glucocorticoid dexamethasone (Dex) abolishes the stimulation of sPLA2-IIA by 25-hydroxycholesterol (25-OH). This inhibition is mediated by the glucocorticoid receptor (GR), which decreases the expression of the oxysterol receptor Pregnane X Receptor (PXR) and interferes with oxysterol signaling by recruiting a common limiting coactivator PGC1α. Consistent with the finding that sPLA2-IIA can partially protect oligodendrocytes against oxysterol-triggered apoptosis, we demonstrate here that the inhibition of sPLA2-IIA by Dex accelerates the apoptotic phenomenon, leading to a shift towards necrosis. We have shown by atomic force microscopy and electron microscopy that 25-OH and Dex alters oligodendrocyte shape and disorganizes the cytoplasm.

          Conclusions/Significance

          Our results provide a new understanding of the cross-talk between oxysterol and glucocorticoid signaling pathways and their respective roles in apoptosis and oligodendrocyte functions.

          Related collections

          Most cited references35

          • Record: found
          • Abstract: found
          • Article: not found

          Cholesterol metabolism in the brain.

          Stephen Turley, J Dietschy (2001)
          The central nervous system accounts for only 2% of the whole body mass but contains almost a quarter of the unesterified cholesterol present in the whole individual. This sterol is largely present in two pools comprised of the cholesterol in the plasma membranes of glial cells and neurons and the cholesterol present in the specialized membranes of myelin. From 0.02% (human) to 0.4% (mouse) of the cholesterol in these pools turns over each day so that the absolute flux of sterol across the brain is only approximately 0.9% as rapid as the turnover of cholesterol in the whole body of these respective species. The input of cholesterol into the central nervous system comes almost entirely from in situ synthesis, and there is currently little evidence for the net transfer of sterol from the plasma into the brain of the fetus, newborn or adult. In the steady state in the adult, an equivalent amount of cholesterol must move out of the brain and this output is partly accounted for by the formation and excretion of 24S-hydroxycholesterol. This cholesterol turnover across the brain is increased in neurodegenerative disorders such as Alzheimer's disease and Niemann-Pick type C disease. Indirect evidence suggests that large amounts of cholesterol also turn over among the glial cells and neurons within the central nervous system during brain growth and neuron repair and remodelling. This internal recycling of sterol may involve ligands such as apolipoproteins E and AI, and one or more membrane transport proteins such as members of the low density lipoprotein receptor family. Changes in cholesterol balance across the whole body may, in some way, cause alterations in sterol recycling and apolipoprotein E expression within the central nervous system, which, in turn, may affect neuron and myelin integrity. Further elucidation of the processes controlling these events is very important to understand a variety of neurodegenerative disorders.
          Article 0 comments Cited 170 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.

            M Bagli, Ingemar Björkhem, U Schlegel … (2000)
            Alzheimer's disease (AD) is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss associated with membrane cholesterol release. 24S-hydroxycholesterol (24S-OH-Chol) is an enzymatically oxidized product of cholesterol mainly synthesized in the brain. We tested the hypothesis that plasma levels of this oxysterol could be used as a putative biochemical marker for an altered cholesterol homeostasis in the brain of AD patients. Thirty patients with clinical criteria for AD, 30 healthy volunteers, 18 depressed patients, and 12 patients with vascular dementia (non-Alzheimer demented) were studied. Plasma concentrations of 24S-OH-Chol were assayed by isotope dilution;-mass spectrometry, cholesterol was measured enzymatically, and apolipoprotein E (apoE) was genotyped by polymerase chain reaction and restricted fragment length polymorphism. The concentration of 24S-OH-Chol in AD and non-Alzheimer demented patients was modestly but significantly higher than in healthy controls and in depressed patients. There was no significant difference in the concentrations of 24S-OH-Chol between depressed patients and healthy controls nor between AD and non-Alzheimer demented patients. The apoE straightepsilon4 allele influences plasma 24S-OH-Chol. However, this influence could be completely accounted for by the elevated plasma cholesterol in apoE4 hetero- or homozygotes. Plasma 24S-OH-Chol levels correlated negatively with the severity of dementia. AD and vascular demented patients appear to have higher circulating levels of 24S-OH-Chol than depressed patients and healthy controls. We speculate that 24S-OH-Chol plasma levels may potentially be used as an early biochemical marker for an altered cholesterol homeostasis in the central nervous system. 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients.
            Article 0 comments Cited 59 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Ligand-activated pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism.

              L Xiang, Veli Ozalp, Upinder S. Bhalla … (2004)
              Previous studies show that feedback inhibition of bile acid production by bile acids is mediated by multiple mechanisms, including activation of pregnane X receptor (PXR). Consistent with these studies, the antibiotic rifampicin, a ligand for human PXR, reduces hepatic bile acid levels in cholestasis patients. To delineate the mechanisms underlying PXR-mediated suppression of bile acid biosynthesis, we examined the functional cross-talk between human PXR and HNF-4, a key hepatic activator of genes involved in bile acid biosynthesis including the cholesterol 7-alpha hydroxylase (CYP7A1) and sterol 12-alpha hydroxylase (CYP8B1) genes. Treatment with rifampicin resulted in repression of endogenous human CYP7A1 expression in HepG2 cells that was reversed by PXR small interfering RNA. The coactivator PGC-1 enhanced transcriptional activity of HNF-4, and this enhancement was suppressed by rifampicin-activated PXR. Endogenous PGC-1 from mouse liver extracts bound to PXR, and recombinant PGC-1 directly interacted with both PXR and HNF-4 in vitro. Rifampicin-dependent interaction of PXR with PGC-1 was shown in cells by coimmunoprecipitation, and intranuclear localization studies using confocal microscopy provided further evidence for this interaction. In chromatin immunoprecipitation studies, rifampicin treatment did not inhibit HNF-4 binding to the native promoters of CYP7A1 and CYP8B1 but resulted in dissociation of PGC-1 and concomitant gene repression. Most interestingly, these rifampicin effects were also observed in the phosphoenolpyruvate carboxykinase gene that contains a functional HNF-4-binding site and is central to hepatic gluconeogenesis. Our study suggests that ligand-activated PXR interferes with HNF-4 signaling by targeting the common coactivator PGC-1, which underlies physiologically relevant inhibitory cross-talk between drug metabolism and cholesterol/glucose metabolism.
              Article 0 comments Cited 41 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2009
                Publication date (Electronic): 26 November 2009
                Volume: 4
                Issue: 11
                Electronic Location Identifier: e8080
                Affiliations
                [1 ]UMR788, Inserm and University Paris-Sud 11, IFR 93, Le Kremlin-Bicêtre, France
                [2 ]UPR 2228, CNRS and University Paris Descartes, IFR95, Paris, France
                [3 ]Cancer, Apoptosis, and Mitochondria Team, UMR8104 CNRS, Institut Cochin, Paris, France
                [4 ]Inserm U800 and University Lille 1, Villeneuve d'Ascq, France
                University of North Dakota, United States of America
                Author notes

                Conceived and designed the experiments: PXP SB CM. Performed the experiments: AT JM PXP SB CS. Analyzed the data: AT PXP SB CS MS CM. Wrote the paper: CM.

                Article
                Publisher ID: 09-PONE-RA-11676R1
                DOI: 10.1371/journal.pone.0008080
                PMC ID: 2779104
                PubMed ID: 19956653
                SO-VID: 292a8200-d316-420c-be8f-4115db7a63f7
                Copyright © Trousson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 15 July 2009
                Date accepted : 5 November 2009
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Cell Biology/Gene Expression
                Subject: Neuroscience/Neuronal and Glial Cell Biology
                Subject: Physiology/Endocrinology

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

                Comments

                Comment on this article

                scite_

                Similar content332

                See all similar

                Cited by9

                See all cited by

                Most referenced authors227

                See all reference authors