Abstract 1952: ABCA1 Deficency Diminishes Dysfunctional HDL And Inhibits Early Atherosclerotic Lesion Development In SR-BI Knockout Mice
Objective: ABCA1 and SR-BI play an essential role in reverse cholesterol transport (RCT) from macrophages in the arterial wall to the liver. The aim of this study was to investigate the effect of combined total-body ABCA1 and SR-BI deficiency on lipoprotein metabolism and atherosclerosis.
Methods & Results: ABCA1/SR-BI double knockout (dKO), ABCA1 KO (AKO), SR-BI KO (SKO), and wildtype (WT) littermates were fed an atherogenic diet for 10 weeks to induce atherosclerosis. Under these conditions, SR-BI deficiency leads to largely increased serum cholesterol (C) levels (SKO: 470±68 mg/dL vs WT: 181±9 mg/dL, p<0.001), due to an impaired removal of HDL-C and VLDL-C, while hampered HDL production in AKO mice resulted in cholesterol levels of only 23±4 mg/dL (p<0.0001). In dKO mice, HDL-C was similarly low as in single AKO mice. Total serum cholesterol levels, however, were 3.8-fold (p<0.001) higher, due to increased VLDL-C levels. Interestingly, more extreme foam cell accumulation was observed in the peritoneal cavity of dKO mice ((30±6%, p<0.01), as compared to WT (1.7±0.2%), SKO (2.5±0.3%), and AKO (5±2%) mice. Combined deletion of ABCA1 and SR-BI thus induces macrophage foam cell formation in vivo. The accumulation of HDL-C and VLDL-C in SKO mice dramatically induced atherosclerotic lesion formation (206±16x103 μm2 vs 12±2x103 μm2 for WT mice, p<0.001)), while lesions were only 33±12x103 μm2 (p<0.05) in AKO and 51±19x103 μm2 (p<0.01) in dKO mice with low HDL-C levels. Thus, despite enhanced foam cell formation in dKO mice, ABCA1 deletion reduces the atherosclerosis susceptibility of SKO mice. Next, the serum atherogenicity was tested by incubation of RAM cells with 3% serum of different types of mice. Serum from SKO mice induced more extreme foam cell formation (89±2%, p<0.001), compared to serum from WT (31±3%), AKO (2.3±0.1%), and dKO (3.1±0.5%) mice. Interestingly, this effect highly correlated with both HDL-C (r=0.98, p<0.0001) and VLDL/LDL-C levels (r=0.96, p<0.0001).
Conclusion: Total-body ABCA1 deficiency inhibits early atherosclerotic lesion development in SR-BI KO mice, which might be attributable to reduced circulating levels of pro-atherogenic HDL. Furthermore, both SR-BI and ABCA1 are essential for maintaining HDL-mediated RCT.