Psychotropic drugs up-regulate the expression of cholesterol transport proteins including ApoE in cultured human CNS- and liver cells.
BACKGROUND
Disturbances in lipid homeostasis and myelination have been proposed in the pathophysiology of schizophrenia and bipolar disorder. We have previously shown that several antipsychotic and antidepressant drugs increase lipid biosynthesis through activation of the Sterol Regulatory Element-Binding Protein (SREBP) transcription factors, which control the expression of numerous genes involved in fatty acid and cholesterol biosynthesis. The aim of the present proof-of-principle study was to investigate whether such drugs also affect lipid transport and export pathways in cultured human CNS and liver cells.


RESULTS
Quantitative PCR and immunoblotting were used to determine the level of lipid transport genes in human glioblastoma (GaMg) exposed to clozapine, olanzapine, haloperidol or imipramine. The effect of some of these drugs was also investigated in human astrocytoma (CCF-STTG1), neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cells. We found significant transcriptional changes of cholesterol transport genes (ApoE, ABCA1, NPC1, NPC2, NPC1L1), which are predominantly controlled by the Liver X receptor (LXR) transcription factor. The up-regulation was observed after 24 to 48 hours of drug exposure, which is markedly delayed as compared to the drug-induced SREBP-controlled stimulation of lipid biosynthesis seen after 6 hours.


CONCLUSIONS
Our data show that stimulation of cellular lipid biosynthesis by amphiphilic psychotropic drugs is followed by a transcriptional activation of cholesterol transport and efflux pathways. Such effects may be relevant for both therapeutic effects and metabolic adverse effects of psychotropic drugs.
Vik-Mo
Audun O
AO
Department of Clinical Medicine, University of Bergen, Dr Einar Martens' Research Group for Biological Psychiatry and Bergen Mental Health Research Center, Norway. audunvik-mo@online.no
Fernø
Johan
J
Skrede
Silje
S
Steen
Vidar M
VM
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D053329:Apolipoprotein E2 / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051779:Sterol Regulatory Element Binding Proteins; D013997:Time Factors; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D053329:Apolipoprotein E2; D011619:Psychotropic Drugs; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases