title: Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice.
abstract: OBJECTIVE
  The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in vivo and in modulating susceptibility to atherosclerosis.
  
  
  METHODS
  Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice.
  
  
  RESULTS
  Interestingly, lack of ABCA2 in macrophages resulted in a diminished lesion size in the aortic root (-24.5%) and descending thoracic aorta (-36.6%) associated with a 3-fold increase in apoptotic cells, as measured by both caspase 3 and TUNEL. Upon oxidized LDL exposure, macrophages from wildtype (WT) transplanted animals developed filipin-positive droplets in lysosomal-like compartments, corresponding to free cholesterol (FC) accumulation. In contrast, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of FC over peripheral regions. The accumulation of neutral sterols in lipid droplets was increased in ABCA2-deficient macrophages, but primarily in cytoplasmic clusters and not in lysosomes. Importantly, apoptosis of oxLDL loaded macrophages lacking ABCA2 was increased 2.7-fold, probably as a consequence of the broad cellular distribution of FC.
  
  
  CONCLUSIONS
  Lack of functional ABCA2 generates abnormalities in intracellular lipid distribution/trafficking in macrophages consistent with its lysosomal sequestering role, leading to an increased susceptibility to apoptosis in response to oxidized lipids and reduced atherosclerotic lesion development.
authors: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands.
authors: Laura
authors: L
authors: Calpe-Berdiel
authors: Ying
authors: Y
authors: Zhao
authors: Marjo
authors: M
authors: de Graauw
authors: Dan
authors: D
authors: Ye
authors: Peter J
authors: PJ
authors: van Santbrink
authors: A Mieke
authors: AM
authors: Mommaas
authors: Amanda
authors: A
authors: Foks
authors: Martine
authors: M
authors: Bot
authors: Illiana
authors: I
authors: Meurs
authors: Johan
authors: J
authors: Kuiper
authors: Jody T
authors: JT
authors: Mack
authors: Miranda
authors: M
authors: Van Eck
authors: Kenneth D
authors: KD
authors: Tew
authors: Theo J C
authors: TJ
authors: van Berkel
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D053148:Caspase 3 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D005372:Filipin / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D020287:In Situ Nick-End Labeling; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D018183:Transplantation Chimera; D014916:Whole-Body Irradiation
chemical_list: D018528:ATP-Binding Cassette Transporters; C498824:Abca2 protein, mouse; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D005372:Filipin; D002784:Cholesterol; C505409:Casp3 protein, mouse; D053148:Caspase 3