Atypical antipsychotic drugs deregulate the cholesterol metabolism of macrophage-foam cells by activating NOX-ROS-PPARγ-CD36 signaling pathway

Chia Hui Chen, Shr Jeng Jim Leu, Chiao Po Hsu, Ching Chian Pan, Song Kun Shyue*, Tzong Shyuan Lee

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Background: Clinical reports indicate that schizophrenia patients taking atypical antipsychotic drugs suffer from metabolism diseases including atherosclerosis. However, the mechanisms underlying the detrimental effect of atypical antipsychotic drugs on atherosclerosis remain to be explored. Methods: In this study, we used apolipoprotein E-deficient (apoe−/−) hyperlipidemic mice and apoe−/−cd36−/− mice to investigate the underlying mechanism of atypical antipsychotic drugs on atherosclerosis and macrophage-foam cells. Results: In vivo studies showed that genetic deletion of cd36 gene ablated the pro-atherogenic effect of olanzapine in apoe−/− mice. Moreover, in vitro studies revealed that genetic deletion or siRNA-mediated knockdown of cd36 or pharmacological inhibition of CD36 prevented atypical antipsychotic drugs-induced oxLDL accumulation in macrophages. Additionally, olanzapine and clozapine activated NADPH oxidase (NOX) to generate reactive oxygen species (ROS) which upregulated the activity of peroxisome proliferator-activated receptor γ (PPARγ) and subsequently elevated CD36 expression. Inhibition of NOX activity, ROS production or PPARγ activity suppressed CD36 expression and abolished the detrimental effects of olanzapine and clozapine on oxLDL accumulation in macrophages. Conclusion: Collectively, our results suggest that atypical antipsychotic drugs exacerbate atherosclerosis and macrophage-foam cell formation by activating the NOX-ROS-PPARγ-CD36 pathway.

Original languageEnglish
Article number154847
JournalMetabolism: Clinical and Experimental
Volume123
DOIs
StatePublished - Oct 2021

Keywords

  • Atherosclerosis
  • Atypical antipsychotic drug
  • CD36
  • Foam cell
  • Reactive oxygen species

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