Abstract
ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.
Highlights
Reverse cholesterol transport (RCT), defined as the transport of accumulated cholesterol from peripheral tissues back to the liver for biliary excretion, plays an important protective role in atherogenesis [1,2]
No significant effect of macrophage ABCA7 deficiency was observed on serum free cholesterol (FC) levels, total cholesterol (TC), triglyceride (TG) or phospholipids (PL) (Fig. 1A)
Increased macrophage ABCA1 expression might counteract the effect of ABCA7 deletion in foam cell formation and atherosclerosis
Summary
Reverse cholesterol transport (RCT), defined as the transport of accumulated cholesterol from peripheral tissues back to the liver for biliary excretion, plays an important protective role in atherogenesis [1,2]. In this process, cholesterol efflux represents a crucial mechanism to maintain cellular lipid homeostasis in macrophages and to prevent pathological foam cell formation, a hallmark of atherosclerosis. ABCA1 promotes the first step in RCT, namely the efflux of cholesterol and phospholipids to lipid-poor apolipoprotein such as apolipoprotein (apo) A-I, thereby initiating the generation of high-density lipoprotein (HDL) [3,4,5]. In addition to ABCA1, macrophage ABCG1 plays a significant role in macrophage lipid homeostasis by inducing cellular cholesterol efflux to mature HDL [10,11]
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