title: Macrophage ABCA5 deficiency influences cellular cholesterol efflux and increases susceptibility to atherosclerosis in female LDLr knockout mice.
abstract: OBJECTIVE
  To determine the role of macrophage ATP-binding cassette transporter A5 (ABCA5) in cellular cholesterol homeostasis and atherosclerotic lesion development.
  
  
  RESULTS
  Chimeras with dysfunctional macrophage ABCA5 (ABCA5(-M/-M)) were generated by transplantation of bone marrow from ABCA5 knockout (ABCA5(-/-)) mice into irradiated LDLr(-/-) mice. In vitro, bone marrow-derived macrophages from ABCA5(-M/-M) chimeras exhibited a 29% (P<0.001) decrease in cholesterol efflux to HDL, whereas a 21% (P=0.07) increase in cholesterol efflux to apoA-I was observed. Interestingly, expression of ABCA1, but not ABCG1, was up-regulated in absence of functional ABCA5 in macrophages. To induce atherosclerosis, the transplanted LDLr(-/-) mice were fed a high-cholesterol Western-type diet (WTD) for 6, 10, or 18weeks, allowing analysis of effects on initial as well as advanced lesion development. Atherosclerosis development was not affected in male ABCA5(-M/-M) chimeras after 6, 10, and 18weeks WTD feeding. However, female ABCA5(-M/-M) chimeras did develop significantly (P<0.05) larger aortic root lesions as compared with female controls after 6 and 10weeks WTD feeding.
  
  
  CONCLUSIONS
  ABCA5 influences macrophage cholesterol efflux, and selective disruption of ABCA5 in macrophages leads to increased atherosclerotic lesion development in female LDLr(-/-) mice.
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, The Netherlands. y.dan@lacdr.leidenuniv.nl
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.forename: Illiana
authors.initials: I
authors.lastname: Meurs
authors.forename: Megumi
authors.initials: M
authors.lastname: Ohigashi
authors.forename: Laura
authors.initials: L
authors.lastname: Calpe-Berdiel
authors.forename: Kim L L
authors.initials: KL
authors.lastname: Habets
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kubo
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nishi
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics
chemical_list: C501079:ABCA5 protein, mouse; D018528:ATP-Binding Cassette Transporters; D008055:Lipids; D011973:Receptors, LDL; D002784:Cholesterol