Abstract
Antipsychotic drugs (APDs) have been reported to induce lipogenic genes. This has been proposed to contribute to their efficacy in treating schizophrenia and other psychiatric disorders, as well as the metabolic side effects often associated with these drugs. The precise mechanism for the lipogenic effects of APDs is unknown, but is believed to involve increased activation of the lipogenic transcription factors, such as sterol regulatory element binding proteins (SREBPs). In a series of experiments in a model cell line, we found that a panel of typical and atypical APDs inhibited transport of lipoprotein-derived cholesterol to the endoplasmic reticulum (ER), which houses the cholesterol homeostatic machinery. APDs belong to the class of cationic amphiphiles and as has been shown for other amphiphiles, caused lipoprotein-derived cholesterol to accumulate intracellularly, preventing it from being esterified in the ER and suppressing SREBP activation. APDs did not activate the liver X receptor, another transcription factor involved in lipogenesis. However, these drugs markedly reduced cholesterol synthesis. This paradoxical result indicates that the upregulation of SREBP-target genes by APDs may not translate to increased cellular cholesterol levels. In conclusion, we have determined that APDs disrupt intracellular trafficking and synthesis of cholesterol, which may have important clinical ramifications.
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Abbreviations
- ACC:
-
acetyl-coenzyme A carboxylase
- APDs:
-
antipsychotic drugs
- CHO:
-
Chinese Hamster Ovary
- ER:
-
endoplasmic reticulum
- FAS:
-
fatty acid synthase
- HMG-CoA:
-
3-hydroxy-3-methylglutaryl coenzyme A
- LDL:
-
low-density lipoprotein
- LPDS:
-
lipoprotein-deficient serum
- LXR:
-
liver X receptor
- NPC:
-
Niemann–Pick type C
- NPC1 :
-
Niemann–Pick disease, type C1, gene
- SOAT-1:
-
sterol O-acyltransferase 1
- SREBPs:
-
sterol regulatory element binding proteins
- TLC:
-
thin layer chromatography
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Acknowledgements
The Brown Lab is supported by grants from the Prostate Cancer Foundation of Australia (PR36) and the National Health and Medical Research Council (568619). We thank the members of the Brown Lab for providing critical feedback.
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Kristiana, I., Sharpe, L., Catts, V. et al. Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol. Pharmacogenomics J 10, 396–407 (2010). https://doi.org/10.1038/tpj.2009.62
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DOI: https://doi.org/10.1038/tpj.2009.62
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