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Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-02-06 , DOI: 10.1038/s41401-019-0212-1 Xue-Mei Liu 1, 2 , Xiao-Min Zhao 1 , Chao Deng 3, 4 , Yan-Ping Zeng 1 , Chang-Hua Hu 1, 2
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-02-06 , DOI: 10.1038/s41401-019-0212-1 Xue-Mei Liu 1, 2 , Xiao-Min Zhao 1 , Chao Deng 3, 4 , Yan-Ping Zeng 1 , Chang-Hua Hu 1, 2
Affiliation
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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.
中文翻译：
辛伐他汀通过抑制肝脏 mTOR 信号通路改善奥氮平诱导的大鼠血脂异常。
第二代抗精神病药物（SGA）引起的代谢异常，如血脂异常，是抗精神病治疗的主要临床问题。积累的证据表明他汀类药物可有效降低 SGA 引起的血脂异常，但其潜在机制尚不清楚。在本研究中，我们探讨了 mTOR 信号传导是否参与奥氮平 (OLZ) 诱导的大鼠血脂异常以及辛伐他汀 (Sim) 联合治疗的降脂作用。模型大鼠接受 OLZ (1.0 mg/kg, tid) 7 周；从第三周开始，一组模型大鼠接受 Sim (3.0 mg/kg, tid) 共治疗 5 周。我们发现 OLZ 治疗显着增加了血浆甘油三酯 (TG) 和总胆固醇 (TC) 水平，并促进了肝脏中的脂质积累，而 Sim 的共同治疗逆转了 OLZ 诱导的血脂异常。OLZ 治疗组肝脏 mTORC1 和 p-mTORC1 表达加速，甾醇调节元件结合蛋白 1c (SREBP1c) 及其靶基因的 mRNA 表达上调，而 Sim 联合治疗改善了这些改变。在 HepG2 细胞中，雷帕霉素（一种 mTOR 抑制剂）显着降低了 OLZ 刺激的肝细胞脂质含量，并通过与上调 SREBP1c 介导的从头脂肪生成相关的机制削弱了 Sim 降低脂质的能力。我们的数据表明，OLZ 诱导血浆和肝脏中的脂质积累，Sim 通过减少 SREBP1c 活化和下调参与脂肪生成的基因表达对 mTOR 信号传导的影响来改善 OLZ 诱导的脂质代谢功能障碍。
更新日期：2019-02-06
中文翻译：
辛伐他汀通过抑制肝脏 mTOR 信号通路改善奥氮平诱导的大鼠血脂异常。
第二代抗精神病药物（SGA）引起的代谢异常，如血脂异常，是抗精神病治疗的主要临床问题。积累的证据表明他汀类药物可有效降低 SGA 引起的血脂异常，但其潜在机制尚不清楚。在本研究中，我们探讨了 mTOR 信号传导是否参与奥氮平 (OLZ) 诱导的大鼠血脂异常以及辛伐他汀 (Sim) 联合治疗的降脂作用。模型大鼠接受 OLZ (1.0 mg/kg, tid) 7 周；从第三周开始，一组模型大鼠接受 Sim (3.0 mg/kg, tid) 共治疗 5 周。我们发现 OLZ 治疗显着增加了血浆甘油三酯 (TG) 和总胆固醇 (TC) 水平，并促进了肝脏中的脂质积累，而 Sim 的共同治疗逆转了 OLZ 诱导的血脂异常。OLZ 治疗组肝脏 mTORC1 和 p-mTORC1 表达加速，甾醇调节元件结合蛋白 1c (SREBP1c) 及其靶基因的 mRNA 表达上调，而 Sim 联合治疗改善了这些改变。在 HepG2 细胞中，雷帕霉素（一种 mTOR 抑制剂）显着降低了 OLZ 刺激的肝细胞脂质含量，并通过与上调 SREBP1c 介导的从头脂肪生成相关的机制削弱了 Sim 降低脂质的能力。我们的数据表明，OLZ 诱导血浆和肝脏中的脂质积累，Sim 通过减少 SREBP1c 活化和下调参与脂肪生成的基因表达对 mTOR 信号传导的影响来改善 OLZ 诱导的脂质代谢功能障碍。
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