Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Ldlr^-/- Mice

OBJECTIVE: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr-/- mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr-/- mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c+ foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin-coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c+ macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. CONCLUSIONS: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr-/- mice.