title: Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport.
abstract: Stearoyl-coenzyme A desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. However, the impact of SCD1 on atherosclerosis remains unclear. The aim of this study was to determine whether SCD1 affects macrophage reverse cholesterol transport (RCT) in mice. Compared to the control, adenoviral-mediated SCD1 overexpression in RAW264.7 macrophages increased cholesterol efflux to HDL, but not to apoA-I, without clear changes in ABCA1, ABCG1 and SR-BI expressions. While knockdown of ABCG1 and SR-BI did not affect the SCD1-induced cholesterol efflux to HDL, SCD1-overexpressing macrophages promoted the formation of both normal- and large-sized HDL in media, accompanying increased apolipoprotein A-I levels in HDL fractions. Transformation to larger particles of HDL was independently confirmed by nuclear magnetic resonance-based lipoprotein analysis. Interestingly, media transfer assays revealed that HDL generated by SCD1 had enhanced cholesterol efflux potential, indicating that SCD1 transformed HDL to a more anti-atherogenic phenotype. To study macrophage RCT in vivo, (3)H-cholesterol-labeled RAW264.7 cells overexpressing SCD1 or the control were intraperitoneally injected into mice. Supporting the in vitro data, injection of SCD1-macrophages resulted in significant increases in (3)H-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the (3)H-tracer distribution of HDL fractions obtained from the mice. In conclusion, macrophage-specific SCD1 overexpression promotes overall RCT through increased cholesterol efflux to HDL, suggesting that macrophage SCD1 achieves an anti-atherogenic effect by enhancing RCT.
authors.affiliation: Department of Internal Medicine, National Defense Medical College, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.forename: Grace Megumi
authors.initials: GM
authors.lastname: Sotherden
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nishida
authors.forename: Haruka
authors.initials: H
authors.lastname: Katamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miura
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.forename: Maki
authors.initials: M
authors.lastname: Iizuka
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Makiko
authors.initials: M
authors.lastname: Yogo
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Komatsu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Chizuko
authors.initials: C
authors.lastname: Maruyama
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D001693:Biological Transport, Active / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D013230:Stearoyl-CoA Desaturase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase