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+/-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.
Basso
Federica
F
Lipoprotein Metabolism Section, NHLBI, NIH, 10 Center Drive, 7N102, Bethesda, MD 20892, USA.
Amar
Marcelo J
MJ
Wagner
Elke M
EM
Vaisman
Boris
B
Paigen
Beverly
B
Santamarina-Fojo
Silvia
S
Remaley
Alan T
AT
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D004036:Diet, Atherogenic; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol