Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport
Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport
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DOI：
10.1016/j.bbalip.2013.05.009
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发表时间：
2013-08-01
影响因子：
4.8
通讯作者：
Ikewaki, Katsunori
中科院分区：
文献类型：
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作者：
Nakaya, Kazuhiro;Ayaori, Makoto;Ikewaki, Katsunori
硬脂酰辅酶A去饱和酶1（SCD 1）是单不饱和脂肪酸合成的限速酶。然而，SCD 1对动脉粥样硬化的影响仍不清楚。本研究的目的是确定SCD 1是否影响小鼠巨噬细胞胆固醇逆向转运（RCT）。与对照组相比，在RAW264.7巨噬细胞中，腺病毒介导的SCD 1过表达增加了胆固醇向HDL的流出，但不增加胆固醇向apoA-I的流出，ABCA 1、ABCG 1和SR-BI表达没有明显变化。虽然敲低ABCG 1和SR-BI并不影响SCD 1诱导的胆固醇流出到HDL，但SCD 1过表达的巨噬细胞促进了培养基中正常和大尺寸HDL的形成，伴随着HDL组分中载脂蛋白A-I水平的增加。通过基于核磁共振的脂蛋白分析独立证实了向更大颗粒HDL的转化。有趣的是，培养基转移试验显示，由SCD 1产生的HDL具有增强的胆固醇流出潜力，表明SCD 1将HDL转化为更具抗动脉粥样硬化性的表型。为了研究体内巨噬细胞RCT，将H-3-胆固醇标记的过表达SCD 1的RAW 264.7细胞或对照腹膜内注射到小鼠中。与对照组相比，注射SCD 1-巨噬细胞导致血浆、肝脏和粪便中H-3-示踪剂显著增加，这支持了体外数据。此外，有一个转向更大的颗粒中的H-3-示踪剂分布的HDL馏分从mice.In结论，巨噬细胞特异性SCD 1过表达促进整体RCT通过增加胆固醇流出到HDL，这表明巨噬细胞SCD 1通过增强RCT实现抗动脉粥样硬化作用。(C)2013爱思唯尔有限公司版权所有。
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, H-3-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 H-3-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the H-3-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. (C) 2013 Elsevier B.V. All rights reserved.