Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol

Kristiana, I., Sharpe, L. J., Catts, V. S., Lutze-Mann, L. H. and Brown, A. J. (2010) Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol. Pharmacogenomics Journal, 10 5: 396-407. doi:10.1038/tpj.2009.62


Author Kristiana, I.
Sharpe, L. J.
Catts, V. S.
Lutze-Mann, L. H.
Brown, A. J.
Title Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol
Journal name Pharmacogenomics Journal   Check publisher's open access policy
ISSN 1470-269X
1473-1150
Publication date 2010-10
Year available 2009
Sub-type Article (original research)
DOI 10.1038/tpj.2009.62
Volume 10
Issue 5
Start page 396
End page 407
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2011
Language eng
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. © 2010 Macmillan Publishers Limited. All rights reserved.
Keyword Antipsychotic drugs
Lipoprotein
Cholesterol
Amphiphile
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 8 December 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
 
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Created: Sun, 24 Oct 2010, 00:04:00 EST