Abstract
Second-generation antipsychotic drug (SGA)-induced metabolic abnormalities, such as dyslipidemia, are a major clinical problem for antipsychotic therapy. Accumulated evidences have shown the efficacy of statins in reducing SGA-induced dyslipidemia, but the underlying mechanisms are unclear. In this study, we explored whether mTOR signaling was involved in olanzapine (OLZ)-induced dyslipidemia as well as the lipid-lowering effects of cotreatment of simvastatin (Sim) in rats. Model rats received OLZ (1.0 mg/kg, t.i.d.) for 7 weeks; from the third week a group of model rats were cotreatment of Sim (3.0 mg/kg, t.i.d.) for 5 weeks. We found that OLZ treatment significantly increased the plasma triglyceride (TG) and total cholesterol (TC) levels, and promoted lipid accumulation in the liver, whereas cotreatment of Sim reversed OLZ-induced dyslipidemia. Hepatic mTORC1 and p-mTORC1 expression was accelerated in the OLZ treatment group, with upregulation of mRNA expression of sterol regulatory element-binding protein 1c (SREBP1c) and its target genes, whereas these alterations were ameliorated by Sim cotreatment. In HepG2 cells, rapamycin (a mTOR inhibitor) significantly reduced the OLZ-stimulated hepatocellular lipid contents and weakened the ability of Sim to lower lipids via a mechanism associated with the upregulation of SREBP1c-mediated de novo lipogenesis. Our data suggest that OLZ induces lipid accumulation in both plasma and liver, and Sim ameliorates OLZ-induced lipid metabolic dysfunction through its effects on mTOR signaling via reducing SREBP1c activation and the downregulation of gene expression involved in lipogenesis. These data provide a new insight into the prevention of metabolic side effects induced by antipsychotic drugs.
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Acknowledgments
This work was supported by grants from the Key Program of Chongqing Science and Technology Research Project (cstc2016shmsxm80102), Venture & Innovation Support Program for Chongqing Overseas Returnees (cx2018089) and the Fundamental Research Funds for the Central Universities, China (No. XDJK2018B037). Chao Deng was supported by a NHMRC (National Health and Medical Research Council) project grant (APP1104184).
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C-HH and X-ML managed the literature searches and designed the experiments. X-MZ performed the animal treatments. X-ML, X-MZ, and Y-PZ performed the lipid, Q-PCR and Western blotting assays. X-ML and CD conducted the statistical analysis and prepared the initial draft of the manuscript. All authors contributed to and approved the final manuscript.
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Liu, Xm., Zhao, Xm., Deng, C. et al. Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway. Acta Pharmacol Sin 40, 1049–1057 (2019). https://doi.org/10.1038/s41401-019-0212-1
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DOI: https://doi.org/10.1038/s41401-019-0212-1
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