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Lifestyle choices play a significant role in the etiology of atherosclerosis. Male <i>Apoe</i>^{&#8722;/&#8722;} mice that develop spontaneous atherosclerotic lesions were fed 0%, 0.3%, and 0.4% mangosteen extracts, composed largely of &#945;-mangostin (MG), for 17 weeks. Body weight gains were significantly decreased in both MG-treated groups compared to the control, but the general condition remained good throughout the study. The levels of total cholesterol (decreased very-low-density lipoprotein in lipoprotein profile) and triglycerides decreased significantly in the MG-treated mice in conjunction with decreased hepatic <i>HMG-CoA</i> synthase and <i>Fatty acid transporter</i>. Additionally, increased serum lipoprotein lipase activity and histopathology further showed a significant reduction in atherosclerotic lesions at both levels of MG exposure. Real-time PCR analysis for macrophage indicators showed a significant elevation in the levels of <i>Cd163</i>, an M2 macrophage marker, in the lesions of mice receiving 0.4% MG. However, the levels of <i>Nos2</i>, associated with M1 macrophages, showed no change. In addition, quantitative immunohistochemical analysis of macrophage subtypes showed a tendency for increased M2 populations (CD68⁺/CD163⁺) in the lesions of mice given 0.4% MG. In further analysis of the cytokine-polarizing macrophage subtypes, the levels of <i>Interleukin13</i> (<i>Il13</i>), associated with M2 polarization, were significantly elevated in lesions exposed to 0.4% MG. Thus, MG could suppress the development of atherosclerosis in <i>Apoe</i>^{&#8722;/&#8722;} mice, possibly through an M2 macrophage-mediated mechanism.