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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.