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

Antipsychotic-induced increase in lipid biosynthesis: activation through inhibition?

“…The resultant reduction in cholesterol biosynthesis may seem paradoxical in light of the well-established antipsychotic-related SREBP-controlled activation of lipid biosynthesis genes ( 11 , 17 ). However, the authors suggest that transcriptional activation of cellular lipogenesis is, in fact, a homeostatic feedback mechanism triggered by reduced cholesterol biosynthesis, which is reinforced by antipsychotic-induced trapping of LDL-derived cholesterol within the endosomes/lysosomes, confi rming formerly published results ( 16 ). In contrast to the reduced cholesterol production, biosynthesis of complex lipids (triglycerides and phospholipids) was increased in the cell cultures during exposure to antipsychotic drugs.…”

Anti-tumor Effects of Penfluridol through Dysregulation of Cholesterol Homeostasis

“…Recently, cholesterol metabolism has become an attractive biochemical target for cancer treatment (Freeman and Solomon, 2004;Llaverias et al, 2011). Kristiana et al reported that in vitro a range of APDs could inhibit cholesterol synthesis in Chinese Hamster Ovary-7 cells with concomitant accumulation of sterol intermediates (Kristiana et al, 2010). They suggested that the dysregulation of cholesterol homeostasis may be an alternative mechanism explanation for APD cytotoxicity to cancer cells; as such drugs induced alteration of those genes that play a major role in regulating cholesterol homeostasis (Wiklund et al, 2010).…”

Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro

“…We previously reported that in both neuroblastoma SH-SY5Y and promyelocytic HL-60 human cell lines, haloperidol inhibited cholesterol biosynthesis, resulting in a decrease in the cell cholesterol content and the accumulation of different sterol intermediates , zymostenol, and cholesta-8,14-dien-3 ␤ -ol] depending on the dose of the drug, suggesting the inhibition of ⌬ 7 -reductase > ⌬ 8,7 -isomerase > ⌬ 14 -reductase enzyme activities in this order ( 15,16 ). By determining the incorporation of radioactive acetate into cholesterol, Kristiana et al ( 17 ) confi rmed this effect of haloperidol and reported that SGAs, such as clozapine, quetiapine, olanzapine, risperidone, and ziprasidone, have the ability to inhibit cholesterol biosynthesis, although the affected steps were not elucidated. In contrast, Lauressergues et al reported that the SGAs clozapine and olanzapine ( 18 ) as well as risperidone ( 19 ) increased cholesterol biosynthesis in primary cultures of rat hepatocytes, whereas other antipsychotics, such as haloperidol, quetiapine, and aripiprazole, did not affect this pathway ( 18 ).…”

“…Antipsychotics are cationic amphiphiles with the potential to interfere with the endosomal/lysosomal pathway ( 16,17 ). Fig.…”