Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells

Ræder, Maria B.; Fernø, Johan; Glambek, Marte; Stansberg, Carl Trygve; Steen, Vidar M.

doi:10.1016/j.neulet.2005.10.096

Cited by 60 publications

(53 citation statements)

References 22 publications

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“…Increase in fatty acid biosynthesis upon treatment with several antipsychotic and antidepressant drugs has been noted before in cell culture assay systems implicating a transcription factor in the mechanism of action of these drugs. 51,52 Replication of findings Generally, similar findings emerged between the two data sets (Figure 2) although the second study was a week shorter. We had fewer subjects on olanzapine and risperidone in set II that could have impacted the statistical significance of some of the findings but not the trends.…”

Section: :5n6supporting

confidence: 59%

Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Kaddurah‐Daouk

McEvoy

Baillie³

et al. 2007

Mol Psychiatry

239

181

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Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform 'lipidomics' that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2-3 weeks with olanzapine (n = 20), risperidone (n = 14) or aripiprazole (n = 16). Patients were recruited in two cohorts (study I, n = 27 and study II, n = 23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.

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Section: :5n6supporting

confidence: 59%

Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Kaddurah‐Daouk

McEvoy

Baillie³

et al. 2007

Mol Psychiatry

239

181

View full text Add to dashboard Cite

show abstract

“…56,57 Considering these observations together with our previous reports that several antipsychotics (and also some antidepressants) activate the SREBP pathway, 5,6,58,59 and that an upregulation of SREBP-controlled fatty acid biosynthesis-related genes is seen in peripheral blood cells from olanzapine-medicated patients, 60 it raises the hypothesis that some antipsychotic drugs may have a beneficial effect on the negative symptoms and cognitive dysfunctions in schizophrenia through a lipogenic activation and secondary actions on the myelination in the brain. We therefore propose to direct more research toward (i) understanding how some of the existing antipsychotic drugs could act on the myelination level or synaptic function in the brain, (ii) identifying genetic or anatomical (e.g.…”

Section: Effects Of Antipsychotic Drugs On Myelinationmentioning

confidence: 79%

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

et al. 2008

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Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 Â 10 À4 for SREBF1 (rs11868035, odd ration (OR) = 1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 Â 10 À5 for SREBF2 (rs1057217, OR = 1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.

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“…9A . These bands were also observed after U18666A treatment sterol-regulatory element binding protein (SREBP) transcription factors ( 40,41 ). Although the mechanism is unknown, the modulation of the SREBP pathway by amitriptyline may be related to the compound-induced accumulation of cholesterol in the late endosomes.…”

Section: Effects Of the Hit Compounds On De Novo Cholesterol Biosynthmentioning

confidence: 97%

Fluorescence image screening for chemical compounds modifying cholesterol metabolism and distribution

Ishitsuka

Saito

Osada

et al. 2011

Journal of Lipid Research

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Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells

Cited by 60 publications

References 22 publications

Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples

Fluorescence image screening for chemical compounds modifying cholesterol metabolism and distribution

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