1. ¹Dr Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health Research Center, Section for Medical Genetics and Molecular Medicine, University of Bergen, Bergen, Norway
2. ²Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse Bergen HF, Norway
3. ³Section of Medical Biochemistry, Institute of Medicine, University of Bergen, Norway

Correspondence: Professor VM Steen, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Helse Bergen HF, Norway. Tel: +47 55975327/55975475; Fax: +47 55975141; E-mail: vidar.martin.steen@helse-bergen.no

Received 2 February 2005; Revised 8 April 2005; Accepted 8 June 2005; Published online 19 July 2005.

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.