No abstract

Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics. 2 Heritability has been demonstrated to play an important role in the etiology, but numerous genetic linkage and association studies have yielded conflicting results, although there are now several promising candidate susceptibility genes. 3 Brain imaging studies of schizophrenic patients have shown various structural and functional abnormalities, including enlargement of the ventricles and volume reductions in specific brain regions, 4,5 even in first episode and drug-naïve subjects. [6][7][8] On the other hand, degenerative histopathological findings are strikingly absent. These observations hint at a neurodevelopmental origin of the disorder (for a review, see Harrison and Lewis 9 and Liddle and Pantelis 10 ).

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-011-0867-2) contains supplementary material, which is available to authorized users.

Hypolipidaemic fatty acid derivatives and polyunsaturated fatty acids decrease concentrations of plasma triacylglycerol by mechanisms that are not fully understood. Because poor susceptibility to beta- and/or omega-oxidation is apparently a determinant of the peroxisome proliferating and hypolipidaemic capacity of fatty acids and derivatives, the relative importance of activation of the peroxisome-proliferator-activated receptor alpha (PPARalpha), fatty acid oxidation and triacylglycerol synthesis were examined. We have compared the effects of differentially beta-oxidizable fatty acids on these parameters in primary cultures of rat hepatocytes. Tetradecylthioacetic acid (TTA), 2-methyleicosapentaenoic acid and 3-thia-octadecatetraenoic acid, which are non-beta-oxidizable fatty acid derivatives, were potent activators of a glucocorticoid receptor (GR)-PPARalpha chimaera. This activation was paradoxically reflected in an substantially increased oxidation of [1-(14)C]palmitic acid and/or oleic acid. The incorporation of [1-(14)C]palmitic acid and/or oleic acid into cell-associated and secreted triacylglycerol was decreased by 15-20% and 30% respectively with these non-beta-oxidizable fatty acid derivatives. The CoA ester of TTA inhibited the esterification of 1, 2-diacylglycerol in rat liver microsomes. Both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) activated GR-PPARalpha. EPA increased the oxidation of [1-(14)C]palmitic acid but DHA had no effect. The CoA ester of EPA inhibited the esterification of 1, 2-diacylglycerol, whereas DHA-CoA had no effect. The ratio between synthesized triacylglycerol and diacylglycerol was lower in hepatocytes cultured with EPA in the medium compared with DHA or oleic acid, indicating a decreased conversion of diacylglycerol to triacylglycerol. Indeed, the incorporation of [1-(14)C]oleic acid into secreted triacylglycerol was decreased by 20% in the presence of EPA. In conclusion, a decreased availability of fatty acids for triacylglycerol synthesis by increased mitochondrial beta-oxidation and decreased triacylglycerol formation caused by inhibition of diacylglycerol acyltransferase might explain the hypolipidaemic effect of TTA and EPA.