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 ABCG1 x LDLr-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 x 10(3) mu m(2), P = 0.01), as measured by cross-sectional analysis in ABCG1 x LDLr-KO mice. Plasma levels for MCP-1 (1.5-fold) and TNF-alpha (1.2-fold) were also increased in ABCG1 x LDLr-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. (c) 2006 Elsevier Inc. All rights reserved.