PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients

Huang, Jing; Xiao, Jianru; Peng, Zhuang; Shao, Ping; Sun, Mengxi; Long, Yujun; Wang, Xiaoyi; Shen, Manjun; Kang, Dongyu; Yang, Ye; Peng, Xing-Jie; Wang, Weiyan; Xie, Peng; Shao, Tiannan; Zhao, Jingping; Wu, Renhua

doi:10.1007/s00213-021-06042-z

Cited by 8 publications

(4 citation statements)

References 27 publications

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“…Interestingly, recent data have identified PCSK9 as a trigger for NAFLD 11 , 43 . Of note, the recent study shows that olanzapine treatment induces PCSK9-mediated dyslipidemia in patients with schizophrenia 44 . Our current findings indicated that olanzapine upregulated the expression of hepatic PCSK9 accompanied by hepatic/hepatocyte steatosis in vivo and in vitro, which is characterized by the increased size and number of lipid droplets within hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Zhu

Ding

Huang

et al. 2022

Sci Rep

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Studies have confirmed that olanzapine, the mainstay treatment for schizophrenia, triggers metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). However, the etiology of olanzapine-induced NAFLD is poorly understood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in NAFLD pathogenesis, and metformin can significantly decrease circulating PCSK9. The purpose of this study was to investigate the role of PCSK9 and explore the therapeutic effect of metformin for olanzapine-associated NAFLD. Olanzapine significantly upregulated PCSK9 and promoted lipid accumulation in mouse livers and HepG2 and AML12 cells. Metformin ameliorated these pathological alterations. PCSK9 upstream regulator liver X receptor α (LXRα) was significantly upregulated in olanzapine-induced NAFLD. LXRα antagonist treatment and LXRα overexpression resulted in a decrease and increase of PCSK9, respectively. Hepatic lipogenesis-associated genes FAS and SCD1 were significantly upregulated in olanzapine-induced NAFLD mice and HepG2 cells overexpressing PCSK9, and genes related to lipid β-oxidation (SCAD and PPARα) were downregulated, while metformin reversed these changes. In addition, we found that LXRα overexpression compromised the effect of metformin on PCSK9 levels and intracellular lipid droplet formation. Taken together, our findings suggest that olanzapine enhances hepatic PCSK9 expression by upregulating LXRα, thereby increasing FAS and SCD1 expression as well as decreasing SCAD and PPARα, and promoting lipid accumulation, and, subsequently, NAFLD, which is ameliorated by metformin.

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Section: Discussionmentioning

confidence: 99%

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Zhu

Ding

Huang

et al. 2022

Sci Rep

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“…In addition, recent systematic reviews have had mixed results for the effects of PCSK9 inhibitors; however, neither of these reviews indicated the effects on patients with SMI or patients taking antipsychotics 31,32 . Further examination of PCSK9 inhibitors should be considered given that expression of PCSK9 is increased within mice dosed with olanzapine 33 …”

Section: Discussionmentioning

confidence: 99%

“…31,32 Further examination of PCSK9 inhibitors should be considered given that expression of PCSK9 is increased within mice dosed with olanzapine. 33 The populations studied could be improved as well. Only four studies included the distribution of patients' race/ ethnicity, and 298 of the 359 patients (83.0%) were white.…”

Section: Discussionmentioning

confidence: 99%

Effects of statin therapies on individuals taking antipsychotics: a systematic review

Ferrell

Ernst

Ferrell

et al. 2023

Journal of Cardiovascular Medicine

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Patients taking antipsychotics to treat severe mental illness may develop adverse effects such as dyslipidaemia. We aimed to provide an update to a previous systematic review showing statin therapy lowering lipid levels in individuals taking antipsychotics, while further identifying any safety concerns or changes in BMI or blood pressure. In August 2022, we searched MEDLINE, Embase, PsycINFO, PubMed and Cochrane Central Register of Controlled Trials for studies on the effects of statins on lipid profile measures for individuals with severe mental illness taking first- or second-generation antipsychotic medications. Data extraction was performed in a masked duplicate fashion. On the basis of article type, the risk of bias in each study was assessed using ROBINS-I or RoB-2. The GRADE criteria were used for certainty assessment. Our initial search returned 396 articles, of which 6 were included in our analysis. Five of them (83.3%) identified a significant change between baseline and posttreatment lipids. Of the articles recording blood pressure, BMI or weight and significant safety concerns, no significant changes were found. The certainty assessment for this systematic review was rated as moderate. A meta-analysis was not performed. We found that studies continue to demonstrate the use of statin therapy in dyslipidaemia prevention and treatment and, in relation, decrease cardiovascular disease risk through significantly reduced LDL-C levels. Patients at risk of developing dyslipidaemias secondary to antipsychotic treatment should be considered for lipid-lowering therapy with a statin. The limited number of studies included and their heterogeneity demonstrate areas for improvement for future research.

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“…For example, olanzapine and clozapine demonstrated the worst side effect profiles, while the most favorable profiles have been shown for aripiprazole, brexiprazole, cariprazine, lurasidone, and ziprasidone [131]. The negative effect of olanzapine on lipid homeostasis has been detected even in patients with a first episode of psychosis [132]. Comparative research revealed that haloperidol and quetiapine can increase lipid levels; ziprasidone probably improves lipid levels, while risperidone can produce both effects [133].…”

Section: Antipsychoticsmentioning

confidence: 99%

Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers

Zorkina,

Ushakova,

Ochneva

et al. 2024

Metabolites

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Lipids are a crucial component of the human brain, serving important structural and functional roles. They are involved in cell function, myelination of neuronal projections, neurotransmission, neural plasticity, energy metabolism, and neuroinflammation. Despite their significance, the role of lipids in the development of mental disorders has not been well understood. This review focused on the potential use of lipids as blood biomarkers for common mental illnesses, such as major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. This review also discussed the impact of commonly used psychiatric medications, such as neuroleptics and antidepressants, on lipid metabolism. The obtained data suggested that lipid biomarkers could be useful for diagnosing psychiatric diseases, but further research is needed to better understand the associations between blood lipids and mental disorders and to identify specific biomarker combinations for each disease.

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PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients

Cited by 8 publications

References 27 publications

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Metformin Ameliorates Hepatic Steatosis induced by olanzapine through inhibiting LXRα/PCSK9 pathway

Effects of statin therapies on individuals taking antipsychotics: a systematic review

Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers

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