Epigenetic histone modulations of PPARγ and related pathways contribute to olanzapine-induced metabolic disorders

Su, Yueqing; Liu, Xuemei; Lian, Jiamei; Deng, Chao

doi:10.1016/j.phrs.2020.104703

Cited by 26 publications

(15 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PPARγ plays a critical role in the monocyte/macrophage differentiation and the formation of macrophage-foam cells [38]. Our study identifies PPARγ as the key transcriptional factor for atypical antipsychotic drug-induced upregulation of CD36, and atherosclerotic progression, which is agreement with the findings by Brandl et al and Su et al that PPARγ pathway may contribute to olanzapine-induced metabolic disorders [39,40]. This notion is also supported by our in vitro observations that inhibition of PPARγ activity attenuates the up-regulation of CD36 and the formation of foam cells by olanzapine and clozapine.…”

Section: Discussionsupporting

confidence: 92%

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

Chen

Leu²,

Hsu

et al. 2021

Metabolism

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 92%

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

Chen

Leu²,

Hsu

et al. 2021

Metabolism

View full text Add to dashboard Cite

show abstract

“…Several studies indicate that youth are more susceptible to metabolic side-effects of SGAs compared to adults [7][8][9]. In our previous studies, we demonstrated that SGAs markedly increase the expression of fatty acid-(such as Fasn and Acc1) and cholesterol biosynthetic genes (such as Hmgcs and Hmgcr, see for Abbreviations complete names) in liver, mediated via activation of the sterol regulatory element-binding proteins (SREBP1 and SREBP2) [10][11][12]. In general, SREBP1 controls the expression of fatty acid biosynthesis genes, while SREBP2 mainly regulates cholesterol biosynthetic genes.…”

Section: Introductionmentioning

confidence: 96%

Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

Liu

Feng

Deng

et al. 2020

BMC Pharmacol Toxicol

Self Cite

View full text Add to dashboard Cite

Background: Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated. Methods: To investigate the efficacy of statin interventions for reversing SGA-induced dyslipidemia, young Sprague Dawley rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O + S), or vehicle (control) for 5 weeks. Results: Olanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O + S co-treatment significantly reversed body weight gain but without significant effects on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O + S co-treatment significantly ameliorated these changes. Pronounced activation of lipogenic gene expression in the liver and down-regulated expression of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) in brown adipose tissue (BAT) was observed in the olanzapine-only group. Interestingly, these protein changes could be reversed by cotreatment with O + B. Conclusions: Simvastatin is effective in ameliorating TC and TG elevated by olanzapine. Modulation of BAT activity by statins could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

show abstract

“…The RNA samples from clinical specimens were extracted using a PARIS™ kit (Thermo Fisher Scientific, Inc.), and the RNA samples were reverse transcribed using Multiscribe™ Reverse Transcriptase (Thermo Fisher Scientific, Inc.) agent. qPCR was subsequently performed according to the protocol described in the referenced studies [ 16 , 17 ]. GAPDH was used as the loading control, and the expression levels of PSA or AR were normalized to the levels of GAPDH mRNA.…”

Section: Methodsmentioning

confidence: 99%

Target Protein for Xklp2 Functions as Coactivator of Androgen Receptor and Promotes the Proliferation of Prostate Carcinoma Cells

Sun

Liang

Xiao

et al. 2022

Journal of Oncology

View full text Add to dashboard Cite

The activation of the androgen receptor (AR) pathway is crucial in the progression of human prostate cancer. Results of the present study indicated that the target protein xenopus kinesin-like protein (TPX2) enhanced the transcription activation of AR and promoted the proliferation of LNCaP (ligand-dependent prostate carcinoma) cells. The protein-protein interaction between AR and TPX2 was investigated using coimmunoprecipitation assays. Results of the present study further demonstrated that TPX2 enhanced the transcription factor activation of AR and enhanced the expression levels of the downstream gene prostate-specific antigen (PSA). TPX2 did this by promoting the accumulation of AR in the nucleus and also promoting the recruitment of AR to the androgen response element, located in the promoter region of the PSA gene. Overexpression of TPX2 enhanced both the in vitro and in vivo proliferation of LNCaP cells. By revealing a novel role of TPX2 in the AR signaling pathway, the present study indicated that TPX2 may be an activator of AR and thus exhibits potential as a novel target for prostate carcinoma treatment.

show abstract

Epigenetic histone modulations of PPARγ and related pathways contribute to olanzapine-induced metabolic disorders

Cited by 26 publications

References 63 publications

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

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

Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

Target Protein for Xklp2 Functions as Coactivator of Androgen Receptor and Promotes the Proliferation of Prostate Carcinoma Cells

Contact Info

Product

Resources

About