Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure
Stearoyl-CoA desaturase inhibits ATP-binding cassette transporter A1-mediated cholesterol efflux and modulates membrane domain structure
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DOI：
10.1074/jbc.m208687200
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发表时间：
2003-02-21
影响因子：
4.8
通讯作者：
Tall, AR
中科院分区：
文献类型：
--
作者：
Sun, Y;Hao, MM;Tall, AR
肝X受体/类维生素A X受体（LXR/RXR）转录因子诱导许多参与细胞胆固醇流出调控的基因，包括ATP结合盒转运蛋白A1（ABCA 1），其介导细胞胆固醇和磷脂主动流出至细胞外受体，如载脂蛋白A-I（apoA-I）。在巨噬细胞LXR/RXR靶基因的筛选中，我们鉴定了硬脂酰辅酶A去饱和酶1和2（Scd 1和Scd 2），随后测试了SCD活性可能调节细胞胆固醇流出的假设。在HEK 293细胞中，ABCA 1与SCD 1或SCD 2的共转染抑制ABCA 1介导的胆固醇流出，但不抑制磷脂流出。在中国仓鼠卵巢（CHO）细胞与SCD 1的中度稳定过表达，胆固醇流出到apoA-I被抑制了73%，而磷脂流出和ABCA 1蛋白水平不变。相比之下，胆固醇流出到HDL 2，这是不依赖于ABCA 1，增加了2倍，在CHO-SCD 1细胞。SCD对胆固醇流出至apoA-I的作用不依赖于酰基辅酶A、胆固醇酰基转移酶（ACAT）活性。SCD活性导致质膜单不饱和脂肪酸（18：1）的含量增加，而饱和脂肪酸（18：0）的损失。如共聚焦显微镜所示，SCD过表达导致质膜中Triton X-100抗性结构域减少，表明膜有序区域减少。这些数据表明，SCD改变膜组织和消耗特定池的膜胆固醇支持ABCA 1介导的流出，而增加胆固醇的可用性被动流出的HDL 2。ABCA 1介导的胆固醇和磷脂流出可能在与高SCD活性相关的病理状态下解偶联，如在高胰岛素血症肥胖小鼠或用LXR激活剂治疗的动物中。
Liver X receptor/retinoid X receptor (LXR/RXR) transcription factors have been found to induce a number of genes involved in the regulation of cellular cholesterol efflux, including the ATP-binding cassette transporter A1 (ABCA1), which mediates the active efflux of cellular cholesterol and phospholipids to extracellular acceptors, such as apolipoprotein A-I (apoA-I). In a screen for macrophage LXR/RXR target genes, we identified stearoyl-CoA desaturases 1 and 2 (Scd1 and Scd2), and subsequently tested the hypothesis that SCD activity might modulate cellular cholesterol efflux. In HEK 293 cells co-transfection of ABCA1 with either SCD1 or SCD2 inhibited ABCA1-mediated cholesterol efflux but not phospholipid efflux. In Chinese hamster ovary (CHO) cells with moderate stable overexpression of SCD1, cholesterol efflux to apoA-I was inhibited by 73%, whereas phospholipid efflux and ABCA1 protein levels were unchanged. In contrast, cholesterol efflux to HDL2, which is not dependent on ABCA1, was increased 2-fold in CHO-SCD1 cells. The effect of SCD on cholesterol efflux to apoA-I was independent of acyl-CoA;cholesterol acyltransferase (ACAT) activity. SCD activity led to an increased content of plasma membrane monounsaturated fatty acids (18:1) at the expense of saturated fatty acids (18:0). As shown by confocal microscopy, SCD overexpression led to a decrease of Triton X-100-resistant domains in the plasma membrane, indicating a decrease in membrane-ordered regions. The data suggest that SCD changes membrane organization and depletes a specific pool of membrane cholesterol supporting ABCA1-mediated efflux, whereas increasing availability of cholesterol for passive efflux by HDL2. ABCA1-mediated cholesterol and phospholipid efflux may be uncoupled in pathological states associated with high SCD activity, as in hyperinsulinemic obese mice, or in animals treated with LXR activators.