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Background Our previous studies demonstrated that Rapamycin overrode the dysregulation of low lipoprotein receptor (LDLR) pathway induced by inflammation.This study was to investigate whether the activation of mammalian target of Rapamycin (mTOR) pathway was involved in lipid accumulation in the aortas of apolipoprotein E knockout (apoE KO) mice.Methods The apoE KO mice fed with Western diet were divided into four groups for eight weeks (n=8, each group): mice with daily distilled water injection (Control), or 8 mg/kg/ q.o.d Sirolimus injection, or daily 10% casein injection, or Sirolimus plus casein injection.Cytokine production in the plasma was measured by enzyme-linked immunosorbent assay.The serum lipid profile in apoE KO mice was measured by clinical biochemistry assay.Foam cell formation and lipid droplets accumulation were checked by hematoxylin-eosin (HE) staining and Oil red O (ORO) staining.The expressions of mTOR pathway associated proteins and the LDLR feedback regulation correlated proteins were examined by immunohistochemical staining,immunofluorescent staining.Results Increased serum amyloid A (SAA) in casein injected mice suggested a successful induction of inflammatory stress.Interestingly, Serum levels of total cholesterol, total triglyceride,LDL, and HDL were significantly decreased in casein injected mice compared to the controls, while these were no difference in Rapamycin treated group compared to the controls.HE and ORO staining demonstrated that inflammatory stress exacerbated formation of foam cells and atherosclerotic plaque, which was correlated with the increased protein expressions of LDLR, sterol regulatory element binding protein-2 (SREBP-2), and SREBP cleavage-activating protein (SCAP).Confocal microscopy observation showed that inflammation enhanced the translocation of SCAP escorting SREBP-2 from the endoplasmic reticulum to the Golgi, thereby activating LDLR gene transcription.Further analysis showed that inflammation increased protein expressions of the mTOR pathway, mTOR, phosphated-mTOR, eukaryotic translation initation factor 4E binding protein 1 (4EBP1),p-4EBP1, ribosomal protein S6 kinase 1 (S6K1), p-S6K1, which were closely associated with the dysregulation of LDLR pathway.Conclusion Inflammation accelerated the progression of atherosclerosis in apoE KO mice via dysregulation of LDLR pathway, which could be mediated by the activation of mTOR pathway.