Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice

BACKGROUND - The peroxisome proliferator-activated receptor-α (PPARα) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARα ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARα expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. METHODS AND RESULTS - To examine the contribution of PPARα expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR) mice were reconstituted with bone marrow from PPARα or PPARα mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPARα→LDLR mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPARα→LDLR mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPARα→LDLR mice. Peritoneal macrophages from PPARα mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARα macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-κB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-κB gene expression levels in vivo in atherosclerotic lesions of PPARα→LDLR mice compared with the lesions of control PPARα→LDLR mice. CONCLUSIONS - These data demonstrate that PPARα expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.