Incremental replacement of saturated fats by n 3 fatty acids in high-fat, high-cholesterol diets reduces elevated plasma lipid levels and arterial lipoprotein lipase, macrophages and atherosclerosis in LDLR / mice

Abstract

Objective: Effects of progressive substitution of dietary n 3 fatty acids (FA) for saturated FA (SAT) on modulating risk factors for atherosclerosis have not been fully defined. Our previous reports demonstrate that SAT increased, but n 3 FA decreased, arterial lipoprotein lipase (LpL) levels and arterial LDLcholesterol deposition early in atherogenesis. We now questioned whether incremental increases in dietary n 3 FA can counteract SAT-induced pro-atherogenic effects in atherosclerosis-prone LDL-receptor knockout (LDLR / ) mice and have identified contributing mechanisms. Methods and results: Mice were fed chow or high-fat diets enriched in SAT, n 3, or a combination of both SAT and n 3 in ratios of 3:1 (S:n 3 3:1) or 1:1 (S:n 3 1:1). Each diet resulted in the expected changes in fatty acid composition in blood and aorta for each feeding group. SAT-fed mice became hyperlipidemic. By contrast, n 3 inclusion decreased plasma lipid levels, especially cholesterol. Arterial LpL and macrophage levels were increased over 2-fold in SAT-fed mice but these were decreased with incremental replacement with n 3 FA. n 3 FA partial inclusion markedly decreased expression of proinflammatory markers (CD68, IL-6, and VCAM-1) in aorta. SAT diets accelerated advanced atherosclerotic lesion development, whereas all n 3 FA-containing diets markedly slowed atherosclerotic progression. Conclusion: Mechanisms whereby dietary n 3 FA may improve adverse cardiovascular effects of high- SAT, high-fat diets include improving plasma lipid profiles, increasing amounts of n 3 FA in plasma and the arterial wall. Even low levels of replacement of SAT by n 3 FA effectively reduce arterial lipid deposition by decreasing aortic LpL, macrophages and pro-inflammatory markers.