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.
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.
Conclusion: 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.
Antipsychotic and antidepressant drugs are imperative in the treatment of schizophrenia and affective disorders.
These drugs exert their therapeutic effects at least in part through perturbation of the dopamine-, noradrenaline- and
serotonin neurotransmitter systems in the brain, but additional molecular mechanisms of action are likely to
contribute to their clinical effect. We have demonstrated that several antipsychotics and antidepressants increase
lipid biosynthesis in cultured human CNS cells.[1–4] This drug-induced stimulation of cellular lipogenesis could
represent a novel mechanism of psychotropic drug action in the brain, since glia-produced lipids, including
cholesterol, play important roles in myelination and synaptogenesis.[5,6] Interestingly, several studies have indicated
disrupted glial function, as well as lipid and myelin abnormalities, in schizophrenia and affective disorders.[7–11] The
drug-mediated lipogenic effect could also be relevant for the associated serious metabolic adverse effects, such as
weight gain and dyslipidemia. Indeed, some of the psychotropic drugs increase the expression of lipid biosynthesis
genes in cultured hepatocytes and adipocytes,[1,3,12–14] as well as in blood cells from olanzapine-treated patients.
The increased lipid biosynthesis is mediated through activation of the sterol regulatory element-binding protein
(SREBP) transcription factors, which control the expression of genes involved in cellular production of cholesterol
(e.g., 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCR) and fatty acids (e.g., fatty acid synthase; FASN and
stearoyl CoA-desaturase; SCD). The SREBP system is sensitive to cationic amphiphilic drugs, such as antipsychotic
and tricyclic antidepressant, through their ability to partly mimic the effects of oxysterols.
FROM: BMC Pharmacology
By: Audun O Vik-Mo; Johan Fernø; Silje Skrede; Vidar M Steen