Abstract 1338: Decreased Atherosclerosis in LDL Receptor Knock-out Mice Transplanted with ABCG1 Deficient Bone Marrow is Associated with Compensatory Induction of Abca1 and apoE Secretion from Macrophages
The ATP binding cassette transporter ABCG1 had been shown to promote cholesterol efflux from macrophages to HDL particles, whereas ABCA1 is responsible for cholesterol efflux to lipid-poor apoA-1 containing particles. The purpose of this study was to investigate the role of ABCG1 in atherogenesis by performing bone marrow (BM) transplantation from female Abcg1−/− and Abcg1+/+ (Control) mice into irradiated male Ldlr−/− mice. We hypothesized that the absence of Abcg1 in macrophages would result in increased atherosclerosis due to impairment of macrophage cholesterol efflux. At 4 weeks after transplantation Abcg1 wild-type alleles were reduced 89% in plasma from Abcg1−/− BM recipients relative to Controls. Atherosclerosis was evaluated after 7 and 11 wks of Western diet feeding. At 7 wks, there was no difference in lesion area between Abcg1−/− (n=10) and Abcg1+/+ (n=10) BM recipients. Surprisingly, after 11 wks Abcg1−/− BM recipients had reduced lesion area compared to Controls (Control: 59651 ± 11805μm2/section, Abcg1−/−: 25206 ± 5713μm2/section, P<0.02), but no differences in cellular content as determined by Mac-3 and α-actin staining. Plasma HDL cholesterol levels were not different at either time point. However, plasma lipoprotein profile analysis revealed an increase in apoE in the VLDL/LDL fraction from Abcg1−/− BM recipients compared to Controls at both 7 and 11 wks. Cell culture experiments with Abcg1−/− macrophages showed increased apoE protein in both media (1.6-fold) and cell lysates (3.9-fold, P<0.01) that was further increased with cholesterol loading and LXR activation (6.3-fold, P<0.01; 7.3-fold, P<0.01, respectively) when compared to Abcg1+/+ cells. LXR target genes Abca1 and Srebp-1c were induced in Abcg1−/− BM recipient macrophages at both 7 (2.0-fold, P<0.001; 1.8-fold, P<0.05, respectively) and 11 wks (1.2-fold, P<0.01; 1.2-fold, P<0.2, respectively). siRNA knockdown of ABCA1 in Abcg1−/− macrophages had no effect on apoE levels in cell lysates, but greatly reduced ApoE secretion by 70% (P<0.05). Our results indicate a compensatory induction of Abca1 and increased apoE secretion in the absence of macrophage Abcg1 that appears to mask the potential anti-atherogenic effects expected with Abcg1 bone marrow transplantation.