Aim As a mixture of various antioxidants, apple polyphenols (APs) are widely investigated for the protective effects against oxidative stress.Epidemiological studies have shown APs can decrease the risk of metabolic diseases and cardiovascular disease (CVD) by lowering the level of low-density lipoprotein (LDL) and total cholesterol.But their impact on atherosclerosis is debated, and the effect of APs on hepatic steatosis remains unclear.In this research, we investigated the effects of APs on atherosclerotic lesions and hepatic lipid metabolism in ApoE-deficient mice, as well as the underlying mechanisms in vitro and in vivo.Methods To evaluate the activities of APs, we used atorvastatin as a control.12-week-old male apolipoprotein E-deficient mice were fed with high fat diet and divided randomly into three groups: control group, atorvastatin group (ATO, 10 mg/kg/d, i.g.) and apple polyphenols group (APs, 100 mg/kg/d, i.g.).Development of atherosclerosis and hepatic steatosis and lipid contents were examined after 12 week treatment.Hepatic gene expression contributing to lipid metabolism was measured to evaluate the mechanism for the lipid-lowering effect of APs.To analyze the antioxidant capacity of APs, catalase (CAT) and superoxide dismutase (SOD) activities in liver were measured.In vitro research, we investigated the effects of APs on the endothelial activation.Rat artery endothelial cells (RAECs) were pretreated with various concentrations of APs followed by lipopolysaccharide (LPS) stimulation for 1 h.The phosphorylation of p38 and ERK1/2, as well as degradation of Iκ Bα and activation of nuclear factor-kappa B (NF-κB) were analyzed by western blot.The effect of APs on reactive oxidative species (ROS) production was also tested measured.The gene transcription and expression of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were evaluated by qRT-PCR and ELISA.Then we tested the effects of APs on the endothelial injury and peripheral blood mononuclear leucocytes (PBMLs) adhesion to RAECs induced by LPS.Results Treatment with APs led to more remarkable reduction of atherosclerotic lesion area and prevention on hepatic steatosis than atorvastatin.The antiatherosclerotic effect was at least partly due to a significant 34.5% (p<0.001) reduction in plasma triglyceride (TG) concentrations, an up to 48.9 % (p<0.04) increase in circulating HDL cholesterol (HDL-C) contents, a significant 26.4% (p<0.03) and 31.8% (p<0.0001) reduction in plasma concentrations of the MCP-1 and VCAM-1.APs modulated lipid metabolism through regulating the transcription of hepatic genes associated and increasing the circulating adiponectin level.The transcription of peroxisome proliferator-activated receptor-α (PPARα) in APs group increased by 90.2% (p<0.05) relative to controls, while the transcriptions of SREBP cleavage-activating protein (SCAP) and sterol regulatory element-binding protein-1c (SREBP-1c) were inhibited by 47.5% (p<0.04) and 59.7% (p<0.03), respectively.As a consequence, the expressions of HMG-CoA Synthase and stearoyl-CoA desaturase (SCD)-1 mRNA reduced by 72.7% (p<0.03) and 71.5% (p<0.005).In addition, accumulation of lipid in the liver was decreased, while antioxidant capacity was improved.The activities of hepatic CAT and SOD increased up to 93.7% (p<0.02) and 10.7% (p<0.02) individually.In vitro research, we observed that APs exerted a potent protective effect on vascular endothelial cells through diminishing reactive oxidative species (ROS) production and suppressing MAPK/NF-κ B signaling pathway in vitro.The dependently suppressive effect of APs on MCP-1, ICAM-1 and VCAM-1 induced by LPS was significant.Consequently, the induction of the adhesion of freshly isolated PBMLs to RAECs was alleviated by APs.Conclusion APs showed a more potent prevention on hepatic steatosis than atorvastatin due to their effective regulation on the antioxidant defense mechanisms of liver and lipid metabolism, as well as endothelium protection in vitro and in vivo, all of which could help mitigate the progression of atherosclerosis.