Reduction in dietary omega-6 polyunsaturated fatty acids: Eicosapentaenoic acid plus docosahexaenoic acid ratio minimizes atherosclerotic lesion formation and inflammatory response in the LDL receptor null mouse

Abstract

Dietary very long chain omega (ω)-3 polyunsaturated fatty acids (PUFA) have been associated with reduced CVD risk, the mechanisms of which have yet to be fully elucidated. LDL receptor null mice (LDLr-/-) were used to assess the effect of different ratios of dietary ω-6 PUFA to eicosapentaenoic acid plus docosahexaenoic acid (ω-6:EPA+DHA) on atherogenesis and inflammatory response. Mice were fed high saturated fat diets without EPA and DHA (HSF ω-6), or with ω-6:EPA+DHA at ratios of 20:1 (HSF R=20:1), 4:1 (HSF R=4:1), and 1:1 (HSF R=1:1) for 32 weeks. Mice fed the lowest ω-6:EPA+DHA ratio diet had lower circulating concentrations of non-HDL cholesterol (25%, P<0.05) and interleukin-6 (IL-6) (44%, P<0.05) compared to mice fed the HSF ω-6 diet. Aortic and elicited peritoneal macrophage (Mϕ) total cholesterol were 24% (P=0.07) and 25% (P<0.05) lower, respectively, in HSF R=1:1 compared to HSF ω-6 fed mice. MCP-1 mRNA levels and secretion were 37% (P<0.05) and 38% (P<0.05) lower, respectively, in elicited peritoneal Mϕ isolated from HSF R=1:1 compared to HSF ω-6 fed mice. mRNA and protein levels of ATP-binding cassette A1, and mRNA levels of TNFα were significantly lower in elicited peritoneal Mϕ isolated from HSF R=1:1 fed mice, whereas there was no significant effect of diets with different ω-6:EPA+DHA ratios on CD36, Mϕ scavenger receptor 1, scavenger receptor B1 and IL-6 mRNA or protein levels. These data suggest that lower ω-6:EPA+DHA ratio diets lowered some measures of inflammation and Mϕ cholesterol accumulation, which was associated with less aortic lesion formation in LDLr-/-mice.

Dietary herring improves plasma lipid profiles and reduces atherosclerosis in obese low-density lipoprotein receptor-deficient mice

“…The dose of EPA and DHA in the herring diet in this study is comparable to previous studies of Ldlr -/-mice using fish oil (34)(35)(36), which ranged between 6 and 14 g of EPA+DHA compared to 11 g EPA+DHA per kilogram of diet used in this study. However, several other parameters differed between the studies; dietary content of cholesterol and lipids, study time and choice of reference diets, rendering direct comparisons on outcome on atherosclerotic development more difficult.…”

“…However, several other parameters differed between the studies; dietary content of cholesterol and lipids, study time and choice of reference diets, rendering direct comparisons on outcome on atherosclerotic development more difficult. Despite these differences in study design, all 3 reported a reduction in atherosclerosis (34)(35)(36). In this study, fatty acid analysis confirmed higher proportion of long-chain n-3 PUFA in livers from the herring-fed mice compared with the beef-fed mice.…”

Impact of Polyunsaturated Fatty Acids on Oxidized Low Density Lipoprotein-Induced U937 Cell Apoptosis

“…The fact that only these membrane PUFA act as substrates for cyclooxygenase and lipoxygenase suggests an increase in the total level of oxygenation processes. As evidenced by the similar effect of EPA and ARA (but not DHA) the present results do not point out the importance of n-3 vs n-6 PUFA, which have controversial effects since a high n-6/n-3 ratio was reported to promote CVD 28,29) . On the contrary, they point out a specific pro-apoptotic effect of 20-carbon PUFA regardless of the series.…”

Nutraceuticals and Prevention of Atherosclerosis: Focus on ω‐3 Polyunsaturated Fatty Acids and Mediterranean Diet Polyphenols

“…Furthermore, it is not yet clear whether it is the absolute low amounts of ω-3 FA in the diet or is the high ratio of ω-6 FA to ω-3 FA-another typical feature of the pro-atherogenic Western diets-to predispose individuals to increased CVD disease [30]. In the LDL receptor-null mice, a commonly used model of atherosclerosis, results point to a relevance of the ratio [31]. Finally, complementary studies on angiogenesis have highlighted a potential anti-angiogenic activity by ω-3 FA in vitro and in vivo [32,33], an effect interpreted as promoting plaque stabilization [34].…”