Abstract
AimABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein (apo) A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored.Methods and ResultsLDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/apoE double KO (dKO) mice, their respective single KO's, and wild-type (WT) controls and were challenged with a high-fat/high-cholesterol diet for 9 weeks. In vitro cholesterol efflux experiments showed no differences between ABCA1 KO and dKO macrophages. The serum non-HDL/HDL ratio in dKO transplanted mice was 1.7-fold and 2.4-fold (p<0.01) increased compared to WT and ABCA1 KO transplanted mice, respectively. The atherosclerotic lesion area in dKO transplanted animals (650±94×103 µm2), however, was 1.9-fold (p<0.01) and 1.6-fold (p<0.01) increased compared to single knockouts (ABCA1 KO: 341±20×103 µm2; apoE KO: 402±78×103 µm2, respectively) and 3.1-fold increased (p<0.001) compared to WT (211±20×103 µm2). When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently protected against atherosclerotic lesion development (p<0.001). Moreover, hepatic expression levels of TNFα and IL-6 were highly induced in dKO transplanted animals (3.0-fold; p<0.05, and 4.3-fold; p<0.001, respectively). In agreement, serum IL-6 levels were also enhanced in ABCA1 KO transplanted mice (p<0.05) and even further enhanced in dKO transplanted animals (3.1-fold as compared to ABCA1 KO transplanted animals; p<0.05).ConclusionsCombined deletion of macrophage ABCA1 and apoE results in a defect in cholesterol efflux and, compared to ABCA1 KO transplanted mice, elevated serum total cholesterol levels. Importantly, these mice also suffer from enhanced systemic and hepatic inflammation, together resulting in the observed augmented atherosclerotic lesion development.
Highlights
Accumulation of cholesterol in macrophages leads to the formation of foam cells, a crucial event in the development of atherosclerotic lesions
Because macrophages are incapable of limiting the uptake of lipoproteins, these cells rely on reverse cholesterol transport (RCT) for maintaining cellular cholesterol homeostasis [1,2]
We have shown that apolipoprotein E as well as the ATP-binding cassette (ABC) transporters A1 and G1 are key players in the efflux of cholesterol from macrophages, the first step in RCT and protection against atherosclerosis [3,4,5]
Summary
Accumulation of cholesterol in macrophages leads to the formation of foam cells, a crucial event in the development of atherosclerotic lesions. We have shown that apolipoprotein (apo) E as well as the ATP-binding cassette (ABC) transporters A1 and G1 are key players in the efflux of cholesterol from macrophages, the first step in RCT and protection against atherosclerosis [3,4,5]. Secreted apoE by macrophages facilitates cellular cholesterol efflux [10] both in the presence and absence of extracellular cholesterol acceptors [11]. Both pro- and anti-atherogenic functions for macrophage apoE have been described [12,13,14,15], we recently showed that macrophage apoE protects against atherosclerotic lesion development, independent of ABCG1 [5] in LDL receptor knockout (LDLr KO) mice. In primary human monocyte-derived macrophages and THP-1 cells it was shown that apoE secretion from macrophages is promoted by ABCA1 [9]
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