Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels

Objective—The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis. Methods and Results—LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156±19×103 &mgr;m2 after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226±30×103 &mgr;m2; P<0.05) and not significantly different from single ABCG1 KO (117±22×103 &mgr;m2) and WT transplanted mice (112±15×103 &mgr;m2). Conclusions—Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts.

[1]  D. Rader,et al.  Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. , 2007, The Journal of clinical investigation.

[2]  David Jelínek,et al.  Characterization of liver disease and lipid metabolism in the Niemann‐Pick C1 mouse , 2007, Journal of cellular biochemistry.

[3]  G. Getz,et al.  Lymphotoxin ß Receptor–Dependent Control of Lipid Homeostasis , 2007, Science.

[4]  T. V. van Berkel,et al.  Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[5]  G. Getz,et al.  Lymphotoxin beta receptor-dependent control of lipid homeostasis. , 2007, Science.

[6]  A. Remaley,et al.  Enhanced ABCG1 expression increases atherosclerosis in LDLr-KO mice on a western diet. , 2006, Biochemical and biophysical research communications.

[7]  G. Hansson,et al.  T Cells in Atherogenesis: For Better or For Worse? , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[8]  A. Vaughan,et al.  ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL Published, JLR Papers in Press, August 10, 2006. , 2006, Journal of Lipid Research.

[9]  A. Tall,et al.  Decreased Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice Transplanted With Abcg1−/− Bone Marrow , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[10]  T. V. van Berkel,et al.  Macrophage ABCG1 Deletion Disrupts Lipid Homeostasis in Alveolar Macrophages and Moderately Influences Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[11]  Andrew C. Li,et al.  Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr−/− and ApoE−/− Mice Transplanted With Abcg1−/− Bone Marrow , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[12]  M. Hayden,et al.  Macrophage ATP-Binding Cassette Transporter A1 Overexpression Inhibits Atherosclerotic Lesion Progression in Low-Density Lipoprotein Receptor Knockout Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[13]  G. Getz,et al.  Diet and Murine Atherosclerosis , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[14]  I. Gelissen,et al.  ABCA1 and ABCG1 Synergize to Mediate Cholesterol Export to ApoA-I , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[15]  T. V. van Berkel,et al.  Scavenger receptors: friend or foe in atherosclerosis? , 2005, Current opinion in lipidology.

[16]  T. V. van Berkel,et al.  Scavenger receptor BI and ATP-binding cassette transporter A1 in reverse cholesterol transport and atherosclerosis , 2005, Current opinion in lipidology.

[17]  M. Rudling,et al.  Lesion Development and Response to Immunization Reveal a Complex Role for CD4 in Atherosclerosis , 2005, Circulation research.

[18]  Paul T. Tarr,et al.  ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. , 2005, Cell metabolism.

[19]  Roger A. Davis,et al.  Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ , 2004 .

[20]  A. Tall,et al.  ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Roger A. Davis,et al.  Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. , 2004, The Journal of clinical investigation.

[22]  G. Getz,et al.  Genetic Background Selectively Influences Innominate Artery Atherosclerosis: Immune System Deficiency as a Probe , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[23]  W. Fung-Leung,et al.  Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  O. Francone,et al.  Increased Atherosclerosis in Hyperlipidemic Mice With Inactivation of ABCA1 in Macrophages , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[25]  C. Schindler,et al.  Lymphocytes are important in early atherosclerosis. , 2001, The Journal of clinical investigation.

[26]  J. Bluestone,et al.  Effect of Immune Deficiency on Lipoproteins and Atherosclerosis in Male Apolipoprotein E-Deficient Mice , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[27]  R. Lawn,et al.  ABCA1 Is the cAMP-inducible Apolipoprotein Receptor That Mediates Cholesterol Secretion from Macrophages* , 2000, The Journal of Biological Chemistry.

[28]  G. Schmitz,et al.  ABC transporters in cellular lipid trafficking , 2000, Current opinion in lipidology.

[29]  C. Gabel,et al.  High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  G. Schmitz,et al.  ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. D. Smith,et al.  T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Daugherty,et al.  Lymphocyte populations in atherosclerotic lesions of apoE -/- and LDL receptor -/- mice. Decreasing density with disease progression. , 1996, Arteriosclerosis, thrombosis, and vascular biology.

[33]  T. Kitagawa,et al.  Time course of hepatic lipids accumulation in a strain of mice with an inherited deficiency of sphingomyelinase. , 1983, The Journal of heredity.

[34]  J. Glomset,et al.  The plasma lecithins:cholesterol acyltransferase reaction. , 1968, Journal of lipid research.