Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

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.