Abstract 49: Myeloid Cell Specific ABCA1 Deletion Does Not Significantly Accelerate Atherogenesis in LDL Receptor Knockout Mice

Abstract

ATP binding cassette transporter A1 (ABCA1) functions as a cellular cholesterol exporter. Macrophage ABCA1 expression is important in reducing cellular cholesterol content and inflammatory response. Bone marrow (BM) transplantation studies suggest that leukocyte ABCA1 protects against atherosclerosis development. However, the in vivo effect of macrophage ABCA1 in atherogenesis is not fully understood due to the presence in BM of other leukocyte populations. Myeloid[[Unable to Display Character: ‐]]Specific ABCA1 Knockout (MSKO) mice in the LDL receptor knockout (LDLrKO) C57BL/6 background were developed to address this question. MSKO/LDLrKO (DKO) and LDLrKO (SKO) mice were fed chow or an atherogenic diet for 10-24wk to examine early to advanced stages of atherosclerosis. Basal (i.e. chow) plasma lipid levels were similar between genotypes, but relative to SKO mice, DKO mice had reduced plasma apoB[[Unable to Display Character: ‐]]containing lipoprotein (apoB Lp) levels throughout the diet-induced atherosclerosis progression phase resulting from decreased hepatic VLDL secretion. Despite a significant reduction in plasma apoB Lp levels, chow and atherogenic diet fed DKO mice had significantly higher cholesterol content in resident peritoneal macrophages and higher plasma proinflammatory cytokine and chemokine levels during atherogenic diet[[Unable to Display Character: ‐]]feeding compared to SKO mice. Aortic cholesterol content was similar between genotypes at early (i.e. 24wk chow-fed) or intermediate (i.e. atherogenic diet for 10wk or 16wk) stages and slightly increased at late stage atherosclerosis (i.e. 24wk atherogenic diet). Aortic root lesion area was also similar for both genotypes after 16wk of atherosclerosis induction. Transplantation of DKO or SKO BM into SKO mice followed by 16wk atherogenic diet feeding also showed similar extent of atherosclerosis. Collectively, these results suggest a novel role for myeloid cell ABCA1 in increasing hepatic VLDL secretion and plasma apoB Lp concentrations in atherogenic diet fed LDLrKO mice that offsets its atheroprotective role in decreasing macrophage cholesterol content and inflammatory response, resulting in no increase in atherosclerosis in its absence.