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

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.

Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences

“…Furthermore, the hepatic expression of mTORc1 decreased after treating with statins. In the liver, mTORc1 is associated with lipid biosynthesis [ 167 ] and it can be overactivated by AAPs [ 168 ]. Statins also reduces many inflammatory indices such as C-reactive protein, interleukin-1β, and tumor necrosis factor-α [ 169 ].…”

Antidepressants- and antipsychotics-induced hepatotoxicity

“…Hepatic abnormalities of lipid and glucose metabolism due to olanzapine have been intensively studied lately. All these studies accumulated evidence that olanzapine has multifaceted effects on hepatic lipid metabolism, including (1) increasing de novo lipogenesis; (2) decreasing lipoprotein internalization and cholesterol clearance; and (3) reducing VLDL secretion through down-regulation of VLDL secretion-related proteins, including apoB and apoE; which all together result with lipid accumulation in the liver (Chen et al 2018 ; Liu et al 2019 ; Mahmoud and El-deek 2019 ; Ren et al 2019a , b ) (Fig. 3 ).…”

Anti-Tumor Effect of Green Tea Extract, Simvastatin and Gamma Radiation on Solid Tumor in Mice

“…The change of tumor size in all groups under study was calculated (Table1) and presented in Figure (3). In the positive control, tumor size reached its high peak after16 days and recorded 825±21.8 mm 3 , but in the case of combination therapy, the tumor size did not exceed 662±12.5mm 3 . There was no significant difference in the rate of tumor size growth till the 8 th day of treatment protocol in all groups, however, in the 11 th day a significant difference occured in the simvastatin group (Pvalue=0.025) and the combination therapy groups (Pvalue = 0.007) compared to the positive control group .…”

“…GLOBOCAN 2018 estimated that there were 18.1 million new cancer cases and 9.6 million cancer deaths in 2018 [2]. Simvastatin is considered a good anti-dyslipidemic drug [3] which stops the cholesterol synthesis pathway (mevalonate pathway), and decreases the risk of atherosclerosis, stroke, coronary artery disease and ischemic heart diseases. It is found that simvastatin has antitumor properties against myeloma cells and induces cell cycle arrest at G0/G1 and G2/M phases through mitochondrial pathway [4].…”