Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport

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• 作者：Kazuhiro Nakaya ; Makoto Ayaori ; Harumi Uto-Kondo ; Grace Megumi Sotherden ; Takafumi Nishida ; Haruka Katamoto ; Yuko Miura ; Shunichi Takiguchi ; Emi Yakushiji ; Maki Iizuka ; Masatsune Ogura ; Makoto Sasaki ; Makiko Yogo ; Tomohiro Komatsu ; Takeshi Adachi ; Chizuko Maruyama ; Katsunori Ikewaki
• 关键词：SCD1 ; stearoyl-coenzyme A desaturase 1 ; RCT ; reverse cholesterol transport ; ABCA1 ; ATP-binding cassette transporter A1 ; ABCG1 ; ATP-binding cassette transporter G1 ; SR-BI ; scavenger receptor class B ; type I
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：1831
• 期：8
• 页码：1402-1411
• 全文大小：1118 K

文摘

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, ³H-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 ³H-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the ³H-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.