title: Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1.
abstract: ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.
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: 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: Suzanne J A
authors.initials: SJ
authors.lastname: Korporaal
authors.forename: A Mieke
authors.initials: AM
authors.lastname: Mommaas
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Josselin
authors.forename: Reeni B
authors.initials: RB
authors.lastname: Hildebrand
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.forename: Ruud
authors.initials: R
authors.lastname: Out
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Giovanna
authors.initials: G
authors.lastname: Chimini
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D016026:Bone Marrow Transplantation; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D055786:Gene Knockout Techniques; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C485856:Abca7 protein, mouse; D008055:Lipids; D011973:Receptors, LDL