Combination of n-3 polyunsaturated fatty acids reduces atherogenesis in apolipoprotein E-deficient mice by inhibiting macrophage activation. (November 2016)

• Record Type: Journal Article
• Authors: Takashima, Akira; Fukuda, Daiju; Tanaka, Kimie; Higashikuni, Yasutomi; Hirata, Yoichiro; Nishimoto, Sachiko; Yagi, Shusuke; Yamada, Hirotsugu; Soeki, Takeshi; Wakatsuki, Tetsuzo; Taketani, Yutaka; Shimabukuro, Michio; Sata, Masataka
• Is Part Of: Atherosclerosis. Volume 254(2016)
• Page Start: 142
• Page End: 150
• Publication Date: 2016-11
• Subjects: Atherosclerosis -- Inflammation -- Lipid raft -- Macrophage -- n-3 poly unsaturated fatty acid -- Toll-like receptor 4; Apoe−/− apolipoprotein E-deficient -- DHA docosahexaenoic acid -- EPA eicosapentaenoic acid -- LPS lipopolysaccharide -- Mac3 macrophage antigen 3 -- MβCD methyl-beta-cyclodextrin -- MCP1 monocyte chemoattractant protein 1 -- MMP9 matrix metalloproteinase 9 -- n-3 PUFA n-3 polyunsaturated fatty acid -- Tfr transferrin receptor -- TLR4 toll-like receptor 4 -- TNFα tumor necrosis factor α -- VCAM1 vascular cell adhesion molecule 1; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2016.10.002
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are major components of n-3 polyunsaturated fatty acids (n-3 PUFAs) which inhibit atherogenesis, although few studies have examined the effects of the combination of EPA and DHA on atherogenesis. The aim of this study was to investigate whether DHA has additional anti-atherosclerotic effects when combined with EPA. Methods: Male 8-week-old apolipoprotein E-deficient ( Apoe −/− ) mice were fed a western-type diet supplemented with different amounts of EPA and DHA; EPA (2.5%, w/w), low-dose EPA + DHA (2.5%, w/w), or high-dose EPA + DHA (5%, w/w) for 20 weeks. The control group was fed a western-type diet containing no n-3 PUFA. Histological and gene expression analysis were performed in atherosclerotic lesions in the aorta. To address the mechanisms, RAW264.7 cells were used. Results: All n-3 PUFA treatments significantly attenuated the development and destabilization of atherosclerotic plaques compared with the control. The anti-atherosclerotic effects were enhanced in the high-dose EPA + DHA group ( p < 0.001), whereas the pure EPA group and low-dose EPA + DHA group showed similar results. EPA and DHA additively attenuated the expression of inflammatory molecules in RAW264.7 cells stimulated with LPS. DHA or EPA + DHA suppressed LPS-induced toll-like receptor 4 (TLR4) expression in lipid rafts on RAW264.7 cells ( p < 0.05). Lipid raft disruption by methyl-β-cyclodextrin suppressed mRNA expression of inflammatory molecules in LPS-stimulated macrophages. Conclusion: n-3 PUFAs suppressed atherogenesis. DHA combined with EPA had additional anti-inflammatory effects and inhibited atherogenesis in Apoe −/− mice. The reduction of TLR4 expression in lipid rafts in macrophages by DHA might be involved in this mechanism, at least partially. Highlights: n-3 PUFAs inhibited the development of atherosclerosis in Apoe −/− mice fed a western-type diet. DHA had additional anti-atherosclerotic effects when combined with EPA in Apoe −/− mice. DHA attenuated pro-inflammatory activation of macrophages by inhibiting TLR4 accumulation into lipid rafts.