PCSK9 Mediates Dyslipidemia Induced by Olanzapine Treatment in Schizophrenia Patients
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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Olanzapine has a negative effect on lipid homeostasis even in patients with a first episode of psychosis.
“The negative effect of olanzapine on lipid homeostasis has been detected even in patients with a first episode of psychosis [132].”
From Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers (2024) · cites this paper as [132]
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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
- ORCID
- 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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