Cited by 16Schizophrenia research and treatmentLipoproteins and Cardiovascular HealthPharmacogenetics and Drug Metabolism

PCSK9 Mediates Dyslipidemia Induced by Olanzapine Treatment in Schizophrenia Patients

Huang, Jing, Xiao, Jingmei, Peng, Zhuang, Shao, Ping, Sun, Mengxi, Long, Yujun, Wang, Xiaoyi, Shen, Manjun +8 more·2022·Psychopharmacology

Abstract

Rationale It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear.Objective To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism.Methods Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia.Results Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10μM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase.Conclusions Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.

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Crossref · 10.1007/s00213-021-06042-z

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Authors
Huang, J., Xiao, J., Peng, Z., Shao, P., Sun, M., Long, Y., Wang, X., Shen, M., Kang, D., Yang, Y., Peng, X., Wang, W., Xie, P., Shao, T., Zhao, J., & Wu, R.
Affiliations
  • Second Xiangya Hospital of Central South University (CN)
  • Hunan University of Traditional Chinese Medicine (CN)
  • Second People Hospital of Hunan (CN)
Corresponding author
Wu, Renrong
Venue
Psychopharmacology
Published
2022-01
Volume
239
Issue
1
Pages
83-91
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
OpenAlex
W4205743333
Cited by
16
References
29
Citations by year
2026: 1 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 2
FWCI
2.44
Type
journal article
Language
en
Open access
closed
Locations
  • Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • the National Nature Science Foundation of China (81622018)
  • Innovative Research Group Project of the National Natural Science Foundation of China (81901401)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
PCSK9, olanzapine, schizophrenia, lipid metabolism, LDL cholesterol, SREBP-1c, SREBP2, hepatic lipid metabolism, LDL receptor degradation, first-episode schizophrenia
MeSH terms
Proprotein Convertase 9, Olanzapine, Animals, Humans, Schizophrenia, Dyslipidemias, Mice

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