Prevention of ATP binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux leads to lipid accumulation in macrophages and atherosclerosis development. C1q tumor necrosis factor-related protein 1 (CTRP1), a conserved paralog of adiponectin, has been shown to aggravate atherosclerosis via its proinflammatory property. However, very little is known about its effects on ABCA1 expression and macrophage lipid accumulation. In the current studies, we found that CTRP1 downregulated ABCA1 expression, inhibited cholesterol efflux to apoA-I and promoted lipid accumulation in THP-1 macrophage-derived foam cells. Forkhead box O1 (FoxO1), a transcriptional repressor of ABCA1, was identified as a direct target of miR-424-5p. Mechanistically, CTRP1 attenuated miR-424-5p levels and then augmented FoxO1 expression in the nucleus, which led to downregulation of ABCA1 expression and inhibition of cholesterol efflux. In conclusion, these findings suggest that CTRP1 restrains cholesterol efflux and facilitates macrophage lipid accumulation through the miR-424-5p/FoxO1/ABCA1 signaling pathway, thereby providing a novel mechanistical insight into its proatherosclerotic action.

中文翻译：

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CTRP1 在 THP-1 巨噬细胞衍生的泡沫细胞中通过 miR-424-5p/FoxO1 通路降低 ABCA1 表达并促进脂质积累

阻止 ATP 结合盒转运蛋白 A1 (ABCA1) 依赖的胆固醇流出导致巨噬细胞中的脂质积累和动脉粥样硬化的发展。C1q 肿瘤坏死因子相关蛋白 1 (CTRP1) 是脂联素的保守旁系同源物，已被证明通过其促炎特性加重动脉粥样硬化。然而，关于它对 ABCA1 表达和巨噬细胞脂质积累的影响知之甚少。在目前的研究中，我们发现 CTRP1 下调 ABCA1 的表达，抑制胆固醇流出到 apoA-I 并促进 THP-1 巨噬细胞衍生的泡沫细胞中的脂质积累。Forkhead box O1 (FoxO1) 是 ABCA1 的转录抑制因子，被确定为 miR-424-5p 的直接靶标。从机制上讲，CTRP1 减弱了 miR-424-5p 水平，然后增强了细胞核中 FoxO1 的表达，这导致 ABCA1 表达的下调和胆固醇流出的抑制。总之，这些发现表明 CTRP1 通过 miR-424-5p/FoxO1/ABCA1 信号通路抑制胆固醇流出并促进巨噬细胞脂质积累，从而为其促动脉粥样硬化作用提供了新的机制见解。