Enhanced ABCG1 Expression Increases Atherosclerosis in LDLr-KO Mice on a Western Diet

ABCG1 promotes cholesterol efflux from cells, but ABCG1-/- bone marrow transplant into ApoE-/- and LDLr-/- mice reduces atherosclerosis. To further investigate the role of ABCG1 in atherosclerosis, ABCG1 transgenic mice were crossed with LDLr-KO mice and placed on a high-fat western diet. Increased expression of ABCG1 mRNA was detected in liver (1.8-fold) and macrophages (2.7-fold) and cholesterol efflux from macrophages to HDL was also increased (1.4-fold) in ABCG1xLDLr-KO vs. LDLr-KO mice. No major differences were observed in total plasma lipids. However, cholesterol in the IDL-LDL size range was increased by approximately 50% in ABCG1xLDLr-KO mice compared to LDLr-KO mice. Atherosclerosis increased by 39% (10.1±0.8 vs 6.1±0.9 % lesion area, p=0.02), as measured by en face analysis, and by 53% (221±98 vs 104±58 ×103 um2, p=0.01), as measured by cross section analysis in ABCG1xLDLr-KO mice. Plasma levels for MCP-1 (1.5-fold) and TNF-alpha (1.2-fold) were also increased in ABCG1xLDLr-KO mice. In summary, these findings suggest that enhanced expression of ABCG1 increases atherosclerosis in LDLr-KO mice, despite its role in promoting cholesterol efflux from cells.