Basso Federica, Amar Marcelo J, Wagner Elke M, Vaisman Boris, Paigen Beverly, Santamarina-Fojo Silvia, Remaley Alan T
Lipoprotein Metabolism Section, NHLBI, NIH, 10 Center Drive, 7N102, Bethesda, MD 20892, USA.
Biochem Biophys Res Commun. 2006 Dec 15;351(2):398-404. doi: 10.1016/j.bbrc.2006.10.044. Epub 2006 Oct 17.
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+/-58x10(3)microm(2), p =0.01), as measured by cross-sectional 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.
ABCG1促进细胞内胆固醇外流，但将ABCG1基因敲除（ABCG1(-/-)）小鼠的骨髓移植到载脂蛋白E基因敲除（ApoE(-/-)）和低密度脂蛋白受体基因敲除（LDLr(-/-)）小鼠体内可减轻动脉粥样硬化。为了进一步研究ABCG1在动脉粥样硬化中的作用，将ABCG1转基因小鼠与低密度脂蛋白受体基因敲除（LDLr-KO）小鼠杂交，并给予高脂西式饮食。与LDLr-KO小鼠相比，ABCG1xLDLr-KO小鼠肝脏中ABCG1 mRNA表达增加（1.8倍），巨噬细胞中增加（2.7倍），巨噬细胞向高密度脂蛋白（HDL）的胆固醇外流也增加（1.4倍）。血浆总脂质未见明显差异。然而，与LDLr-KO小鼠相比，ABCG1xLDLr-KO小鼠中IDL-LDL大小范围内的胆固醇增加了约50%。通过正面分析测量，ABCG1xLDLr-KO小鼠的动脉粥样硬化增加了39%（病变面积为10.1±0.8 vs 6.1±0.9%，p=0.02），通过横截面分析测量增加了53%（221±98 vs 104±58x10(3)平方微米，p =0.01）。ABCG1xLDLr-KO小鼠中单核细胞趋化蛋白-1（MCP-1）（1.5倍）和肿瘤坏死因子-α（TNF-α）（1.2倍）的血浆水平也升高。总之，这些发现表明，尽管ABCG1具有促进细胞内胆固醇外流的作用，但ABCG1表达增强会增加LDLr-KO小鼠的动脉粥样硬化。
