title: The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis.
abstract: OBJECTIVE
  As ABCG1 plays a role in cholesterol efflux, macrophage ABCG1 expression has been suggested to protect against atherosclerosis. However, we and others observed varying effects of ABCG1 deficiency on atherosclerotic lesion size. The objective of this study was to define the effect of ABCG1 deficiency during atherosclerotic lesion progression in LDL receptor knockout (LDLr(-/-)) mice.
  
  
  RESULTS
  ABCG1(-/-)/LDLr(-/-) and ABCG1(+/+)/LDLr(-/-) littermates were fed a Western-type diet for 10 and 12 weeks in order to study the effect of ABCG1 deficiency in the exponential phase of atherosclerotic lesion formation. At 10 weeks of diet feeding, a significant 1.5-fold increase in early atherosclerotic lesion size (130±12×10(3) μm(2)) was observed in ABCG1(-/-)/LDLr(-/-) mice compared to ABCG1(+/+)/LDLr(-/-) mice (88±11×10(3) μm(2); p<0.05). Interestingly, in more advanced lesions, induced by 12 weeks of WTD feeding, ABCG1(-/-)/LDLr(-/-) mice showed a significant 1.7-fold decrease in atherosclerotic lesion size (160±20×10(3) μm(2) vs 273±19×10(3) μm(2) in control mice; p<0.01), indicating that in the ABCG1(-/-)/LDLr(-/-) mice progression of lesion formation is retarded as compared to ABCG1(+/+)/LDLr(-/-) mice. In addition, correlation analysis performed on 7 independent published studies and the current study confirmed that ABCG1 is atheroprotective in early lesions, while the development of advanced lesions is stimulated.
  
  
  CONCLUSIONS
  It appears that the effect of ABCG1 deficiency on lesion development in LDLr(-/-) mice depends on the stage of atherogenesis, whereby the absence of ABCG1 leads to increased lesions at sizes<167×10(3) μm(2) while in more advanced stages of atherosclerosis enhanced apoptosis and/or compensatory mechanisms lead to retarded lesion progression.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands.
authors.forename: Illiana
authors.initials: I
authors.lastname: Meurs
authors.forename: Bart
authors.initials: B
authors.lastname: Lammers
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ruud
authors.initials: R
authors.lastname: Out
authors.forename: Reeni B
authors.initials: RB
authors.lastname: Hildebrand
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D008074:Lipoproteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol