Abstract：
Cholesterol efflux from foam cells in atherosclerotic plaques is crucial for reverse cholesterol transport (RCT), an important antiatherogenic event. ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, are key receptors in the cholesterol efflux pathway. C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly discovered adipokine and exhibits an atheroprotective activity. However, the role of CTRP9 in RCT still remains unknown. In this work, we investigated the effect of subcutaneous administration of CTRP9 protein on RCT and atherosclerotic lesion formation in ApoE-/- mice fed with a high-fat diet. CTRP9-dependent regulation of cholesterol efflux and ABC transporters in RAW 264.7 foam cells was determined. Our results showed that CTRP9 protein decreased atherosclerotic lesions, increased cholesterol efflux, and upregulated liver ABCA1 and ABCG1 expression in ApoE-/- mice. CTRP9 treatment dose-dependently increased mRNA and protein expression of ABCA1, ABCG1, and LXR-α in RAW 264.7 foam cells. Moreover, the expression and phosphorylation of AMPK was potentiated upon CTRP9 treatment. Notably, CTRP9-induced cholesterol efflux and upregulation of ABCA, ABCG1, and LXR-α were impaired when AMPK was knocked down. AMPK depletion restored cholesterol accumulation in CTRP9-treated RAW 264.7 cells. Taken together, subcutaneous injection is an effective novel delivery route for CTRP9 protein, and exogenous CTRP9 can facilitate cholesterol efflux and promote RCT in an animal model of atherosclerosis. The atheroprotective activity of CTRP9 is mediated through the activation of AMPK signaling.
摘要：
胆固醇从动脉粥样硬化斑块中的泡沫细胞流出对于胆固醇逆向转运（RCT）至关重要，一个重要的抗动脉粥样硬化事件。ATP结合盒（ABC）转运蛋白，ABCA1和ABCG1是胆固醇流出途径中的关键受体。C1q/肿瘤坏死因子相关蛋白9（CTRP9）是一种新发现的脂肪因子，具有动脉粥样硬化保护活性。然而,CTRP9在RCT中的作用尚不清楚.在这项工作中,我们研究了在高脂饮食喂养的ApoE-/-小鼠中皮下施用CTRP9蛋白对RCT和动脉粥样硬化病变形成的影响。确定了RAW264.7泡沫细胞中胆固醇流出和ABC转运蛋白的CTRP9依赖性调节。我们的结果显示CTRP9蛋白降低动脉粥样硬化病变,胆固醇流出增加，并上调ApoE-/-小鼠肝脏ABCA1和ABCG1的表达。CTRP9处理剂量依赖性地增加RAW264.7泡沫细胞中ABCA1、ABCG1和LXR-α的mRNA和蛋白表达。此外，CTRP9处理后,AMPK的表达和磷酸化增强.值得注意的是,CTRP9诱导的胆固醇流出和ABCA的上调，当AMPK敲低时，ABCG1和LXR-α受损。AMPK耗竭恢复了CTRP9处理的RAW264.7细胞中的胆固醇积累。一起来看,皮下注射是CTRP9蛋白有效的新型递送途径,外源性CTRP9可以促进动脉粥样硬化动物模型的胆固醇流出和RCT。CTRP9的动脉粥样硬化保护活性是通过激活AMPK信号介导的。
