Decreased atherosclerosis in low-density lipoprotein receptor knockout mice transplanted with Abcg1-/- bone marrow.
OBJECTIVE
Recent studies indicate that the ATP-binding cassette transporter ABCG1 can promote cholesterol efflux from macrophages to high-density lipoprotein. This study was designed to assess the in vivo role of macrophage ABCG1 in atherosclerosis.


RESULTS
Bone marrow from Abcg1-/- mice was transplanted into irradiated Ldlr-/- recipients, and atherosclerosis was evaluated by aortic root assay after 7 or 11 weeks of feeding on a Western diet. After 7 weeks, there was no difference in lesion area in mice receiving either wild-type or Abcg1-/- bone marrow, whereas after 11 weeks, lesion area was moderately but significantly reduced in Abcg1-/- recipients. ABCG1-deficient peritoneal macrophages showed induction of several liver X receptor target genes, such as Abca1 and Srebp1c, and a dramatic increase in apolipoprotein E (apoE) protein both in cell media and lysates, without parallel change in apoE mRNA. Abca1 knockdown prevented the increase in apoE secretion but had minimal effects on apoE accumulation in cell lysates of Abcg1-/- macrophages. Plasma apoE levels were markedly increased in recipients of Abcg1-/- bone marrow.


CONCLUSIONS
These studies reveal an inverse relationship between Abcg1 expression and apoE accumulation and secretion in macrophages. The reduced atherosclerosis in recipients of Abcg1-deficient bone marrow may be explained by induction of Abca1 and an associated increase in macrophage apoE secretion.
Ranalletta
Mollie
M
Division of Molecular Medicine, Department of Medicine, Columbia University, 630 West 168th St, New York, NY 10032, USA. mr2375@columbia.edu
Wang
Nan
N
Han
Seongah
S
Yvan-Charvet
Laurent
L
Welch
Carrie
C
Tall
Alan R
AR
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D050197:Atherosclerosis / Q000473:pathology*; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism; D003470:Culture Media / Q000378:metabolism; D015870:Gene Expression; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency*
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D003470:Culture Media; D008074:Lipoproteins; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D002784:Cholesterol