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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.

Pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-1beta (IL- 1beta), tumour necrosis factor-alpha (TNF-alpha) and chemokine interleukin-8 (IL-8) may play a significant role in the regulation of bacterial corneal infection. The aim of this study was to investigate the gene expression of these four mediators in a human corneal epithelial cell line challenged with Pseudomonas aeruginosa within 12 h. Human corneal epithelial monolayers were colonized with P. aeruginosa strains Paerl, 6206 and 6294. Expression of IL-6, IL-8, IL-1beta and TNF-alpha was analysed using semi-quantitative reverse transcription-polymerase chain reaction. Results showed that both IL-6 and IL-8 mRNA were expressed very early (4 h) during bacterial colonization and remained at high levels until the end of the experiment. Expression of IL-1beta and TNF-alpha mRNA appeared at 8 h after bacterial stimulation. No expression of IL-8, IL-1beta and TNF-alpha mRNA was observed in unstimulated cells. Interleukin-6 mRNA was expressed at low levels in unstimulated cells. In conclusion, bacterial colonization of human corneal epithelial cells induced expression of IL-6 and IL-8 mRNA earlier and at higher levels than IL-1beta and TNF-alpha mRNA.