Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Eibinger, G.
On the Role of 25-Hydroxycholesterol in Astrocytoma Growth
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2014. pp. 141
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- Autor*innen der Med Uni Graz:
- Eibinger Gerald
- Betreuer*innen:
- Kratky Dagmar
- Sattler Wolfgang
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- Abstract:
- The first part of the present work deals with production and effects of 25-hydroxycholesterol (25-OHC) in glioblastoma multiforme (GBM). GBM is the most common malignant primary brain tumor and is invariably fatal to affected patients. Oxysterols belong to a class of bioactive lipids that are implicated in neurological diseases and are associated with various types of cancer. We investigated expression and transcriptional regulation of cholesterol-25-hydroxylase (CH25H) in human A172, U87MG and GM133 glioblastoma cell lines. Transcription and translation of CH25H was upregulated in response to TNFa and IL1ß. To determine whether 25-OHC acts as chemoattractant for tumor-associated macrophages the human THP-1 monoblastic leukemia line was treated with varying amounts of the oxysterol. Experiments revealed that 25-OHC and lipid extracts iso-lated from GM133-conditioned medium induce chemotactic migration of THP-1 cells. In response to exogenously added 25-OHC, THP-1 cells reorganize intermediate filament-associated vimentin to more cortical and polarized structures. Using RNA interference, it could be demonstrated that G protein-coupled receptor 183 (EBI2) contributes to 25-OHC-mediated chemotactic migration of THP-1 cells. These in vitro data indicate that GBM-derived and secreted 25-OHC may be involved in the recruitment of immune-competent cells to a tumor via EBI2. The second part of the work revealed in vivo effects of lipopolysaccharide (LPS) on lipid composition with respect to fatty acids and oxysterols in plasma and brain of C57/Bl6 mice. Endotoxemia resulting in increased serum triglyceride levels could be detected (accompanied by increased linoleic acid in serum), as well as increased total serum cholesterol and oxysterol levels. All observed effects were less pronounced in the brain. Nevertheless an approx. 20% increase of 24S-OHC, 25-OHC and 27-OHC could be detected in murine brain in response to peripheral LPS.