Apple Polyphenols Decrease Atherosclerosis and Hepatic Steatosis in ApoE-/- Mice through the ROS/MAPK/NF-κB Pathway

Nutrients. 2015 Aug 24;7(8):7085-105. doi: 10.3390/nu7085324.


In this study, we examined the effects of apple polyphenols (APs) on hyperlipidemia, atherosclerosis, hepatic steatosis and endothelial function and investigated the potential mechanisms. ApoE(-/-) mice were fed a western-type diet and orally treated with APs (100 mg/kg) or atorvastatin (10 mg/kg) for 12 weeks. Hyperlipidemia and atherosclerosis in the aortic sinuses and, and hepatic lipidosis were measured. The treatment with APs or atorvastatin induced a remarkable reduction in the atherosclerotic lesions and hepatic steatosis and decreased the levels of low-density lipoprotein, triglyceride, CCL-2 and VCAM-1 levels in the plasma. Conversely, the APs significantly increased the plasma levels of high-density lipoprotein (HDL) cholesterol and markedly up-regulated the glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) levels in liver tissues. Moreover, the APs treatment modulated lipid metabolism by up-regulating the transcription of associated hepatic genes including PPARα, while down-regulating the transcription of SCAP and its downstream genes associated with lipid synthesis in the liver. Histological assessment showed that the APs treatment also reduced the macrophage infiltration in the aortic root plaque and the inflammatory cells infiltrations to the liver tissues. Moreover, we confirmed that the APs treatment greatly reduced the ox-LDL-induced endothelial dysfunction and monocyte adhesion to rat aortic endothelial cells (RAECs). Mechanistically, the APs treatment suppressed the ROS/MAPK/NF-κB signaling pathway, and consequently, reduced CCL-2, ICAM-1 and VCAM-1 expression. Our results suggest that the APs are a beneficial nutritional supplement for the attenuation of atherosclerosis.

Keywords: ApoE−/−mice; apple polyphenols; atherosclerosis; atorvastatin; hepatic steatosis; oxidative stress; vascular Inflammation; western-type diet.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / genetics
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Atherosclerosis / prevention & control*
  • Cell Adhesion / drug effects
  • Cell Line
  • Cell Survival / drug effects
  • Chemokine CCL2 / blood
  • Chemokine CCL2 / genetics
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Fatty Liver / prevention & control*
  • Intercellular Adhesion Molecule-1 / blood
  • Intercellular Adhesion Molecule-1 / genetics
  • Lipoproteins, LDL / blood
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Malondialdehyde / metabolism
  • Malus / chemistry*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Polyphenols / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction
  • Vascular Cell Adhesion Molecule-1 / blood
  • Vascular Cell Adhesion Molecule-1 / genetics


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 protein, mouse
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Lipoproteins, LDL
  • NF-kappa B
  • Polyphenols
  • Reactive Oxygen Species
  • Vascular Cell Adhesion Molecule-1
  • oxidized low density lipoprotein
  • Intercellular Adhesion Molecule-1
  • Malondialdehyde
  • Mitogen-Activated Protein Kinases