Simvastatin improves olanzapine-induced dyslipidemia in rats through inhibiting hepatic mTOR signaling pathway

Xue-mei Liu1,2, Xiao-min Zhao1, Chao Deng3,4, Yan-ping Zeng1, Chang-hua Hu1,2
1 School of Pharmaceutical Sciences, Southwest University, Chongqing 400715, China
2 Engineer Research Center of Chongqing Pharmaceutical Process and Quality Control, Chongqing 400715, China
3 School of Medicine, University of Wollongong, Wollongong 2522 NSW, Australia
4 Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong 2522 NSW, Australia
Correspondence to: Chang-hua Hu:,
DOI: 10.1038/s41401-019-0212-1
Received: 29 September 2018
Accepted: 7 January 2019
Advance online: 6 February 2019


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.
Keywords: olanzapine; dyslipidemia; simvastatin; SREBP1c; de novo fatty acid synthesis; mTOR signaling pathway

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