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Objective— Macrophage endothelial lipase (EL) is associated with increased atherosclerosis and inflammation. Because of their anti-inflammatory properties we hypothesized that n-3 fatty acids, in contrast to saturated fatty acids, would lower macrophages and arterial EL and inflammatory markers. Methods and Results— Murine J774 and peritoneal macrophages were incubated with eicosapentaenoic acid or palmitic acid in the presence or absence of lipopolysaccaride (LPS). LPS increased EL mRNA and protein. Palmitic acid alone or with LPS dose-dependently increased EL mRNA and protein. In contrast, eicosapentaenoic acid dose-dependently abrogated effects of LPS or palmitic acid on increasing EL expression. EL expression closely linked to peroxisome proliferator activated receptor (PPAR)γ expression. Eicosapentaenoic acid blocked rosiglitazone (a PPARγ agonist)-mediated EL activation and GW9662 (a PPARγ antagonist)-blocked palmitic acid-mediated EL stimulation. Eicosapentaenoic acid alone or with LPS blunted LPS-mediated stimulation of macrophage proinflammatory interleukin-6, interleukin-12p40, and toll-like receptor-4 mRNA and increased anti-inflammatory interleukin-10 and mannose receptor mRNA. In vivo studies in low density lipoprotein receptor knockout mice showed that high saturated fat rich diets, but not n-3 diets, increased arterial EL, PPARγ, and proinflammatory cytokine mRNA. Conclusion— n-3 fatty acids, in contrast to saturated fatty acids, decrease EL in parallel with modulating pro- and anti-inflammatory markers, and these effects on EL link to PPARγ.

Objective— To determine whether n-3 fatty acids (n-3) influence arterial cholesterol delivery and lipoprotein lipase (LpL) levels in insulin-resistant mice. Methods and Results— Insulin resistance contributes to risk of cardiovascular disease. It was previously reported that saturated fat (SAT) diets increased, but n-3 diets decreased, arterial low-density lipoprotein (LDL) cholesterol deposition from LDL total and selective uptake; this was associated with increased or decreased arterial LpL, respectively. Insulin receptor transgenic knockout mice (L1) were fed a chow, SAT, or n-3 diet for 12 weeks. Double-fluorescent boron dipyrromethene (BODIPY)–cholesteryl ester (CE) and Alexa dye-labeled human LDL were injected to separately trace LDL-CE and LDL–apolipoprotein B whole particle uptake. In contrast to SAT, n-3 diets markedly reduced all plasma lipids, ameliorating progression of insulin resistance. As opposed to SAT, n-3 reduced arterial LDL uptake, CE deposition, and selective uptake. Disparate patterns of CE deposition between diets were comparable with arterial LpL distribution; SAT induced high LpL levels throughout aortic media; LpL was limited only to intima in n-3–fed mice. Conclusion— n-3 diets diminish arterial LDL-cholesterol deposition in mice with insulin resistance, and this is associated with changes in arterial LpL levels and distribution.

Objectives— We previously reported that saturated fat (SAT)-enriched diets increase arterial cholesteryl ester (CE) deposition, especially from LDL-selective uptake (SU), and this was associated with increased arterial lipoprotein lipase (LpL). We now question how n-3 fatty acid rich diets influence arterial cholesterol delivery and arterial LpL levels. Methods and Results— C57BL/6 mice were fed chow or eucaloric high-fat diets enriched in SAT or fish oil (n-3) for 12 weeks, and then injected with double radiolabeled or fluorescent-labeled human LDL to separately trace LDL-CE and LDL-apoB uptake. SAT and n-3 diets increased plasma cholesterol levels similarly; n-3 diets lowered plasma triglyceride concentrations. SAT increased arterial LDL-SU with significantly higher CE infiltration into aortic media. In contrast, n-3 markedly reduced total LDL uptake and CE deposition and abolished SU with LDL localized only in aortic intima. Disparate patterns of CE deposition between diets were consistent with distribution of arterial LpL—SAT diets induced higher LpL levels throughout the aorta; n-3 diets decreased LpL levels and limited LpL expression to the aortic intima. Conclusions— n-3 rich diets decrease arterial total LDL delivery and abrogate LDL-SU in parallel with changing arterial wall LpL expression and distribution.