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.
Fernø
J
J
Dr Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health Research Center, Section for Medical Genetics and Molecular Medicine, University of Bergen, Norway.
Raeder
M B
MB
Vik-Mo
A O
AO
Skrede
S
S
Glambek
M
M
Tronstad
K-J
KJ
Breilid
H
H
Løvlie
R
R
Berge
R K
RK
Stansberg
C
C
Steen
V M
VM
D014150:Antipsychotic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D003024:Clozapine / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma; D006220:Haloperidol / Q000494:pharmacology*; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation
D014150:Antipsychotic Agents; D005227:Fatty Acids; D012313:RNA; D002784:Cholesterol; D064429:Fatty Acid Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase; D003024:Clozapine; D006220:Haloperidol