MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
Department of Physiology, National Yang-Ming University, Taipei, Taiwan.
Acta Physiol (Oxf). 2019 Mar;225(3):e13209. doi: 10.1111/apha.13209. Epub 2018 Nov 19.
CCN family member 1 (CCN1) is an extracellular matrix cytokine and appears in atherosclerotic lesions. However, we have no evidence to support the role of CCN1 in regulating cholesterol metabolism and atherosclerosis.
Apolipoprotein E-deficient (apoE ) mice were used as in vivo model. Oxidized low-density lipoprotein (oxLDL)-induced macrophage-foam cells were used as in vitro model. RT-PCR and western blot analysis were used for evaluating gene and protein expression, respectively. Conventional assay kits were used for assessing the levels of cholesterol, triglycerides, and cytokines.
We show predominant expression of CCN1 in foamy macrophages in atherosclerotic aortas of apoE mice. In apoE mice, CCN1 treatment worsened hyperlipidaemia, systemic inflammation, and the progression of atherosclerosis. In addition, CCN1 decreased the capacity of reverse cholesterol transport and downregulated the protein expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in atherosclerotic aortas. Notably, CCN1 decreased the protein expression of cholesterol clearance-related proteins, including ABCG5, ABCG8, liver X receptor α (LXRα), cholesterol 7α-hydrolase and LDL receptor in liver, and exacerbated hepatic lipid accumulation. In macrophages, treatment with oxLDL increased CCN1 expression. Inhibition of CCN1 activity by neutralizing antibody or small interfering RNA attenuated the oxLDL-induced lipid accumulation. In contrast, cotreatment with CCN1 or overexpression of CCN1 augmented oxLDL-induced lipid accumulation by impairing apolipoprotein AI- and high-density lipoprotein-dependent cholesterol efflux, which was attributed to downregulation of LXRα-dependent expression of ABCA1 and ABCG1.
Our findings suggest that CCN1 plays a pivotal role in regulating cholesterol metabolism and the development of atherosclerosis.
CCN 家族成员 1（CCN1）是一种细胞外基质细胞因子，存在于动脉粥样硬化病变中。然而，我们没有证据表明 CCN1 在调节胆固醇代谢和动脉粥样硬化中发挥作用。
使用载脂蛋白 E 缺陷（apoE）小鼠作为体内模型。使用氧化型低密度脂蛋白（oxLDL）诱导的巨噬细胞泡沫细胞作为体外模型。分别采用 RT-PCR 和 Western blot 分析评估基因和蛋白表达。采用常规检测试剂盒评估胆固醇、甘油三酯和细胞因子水平。
我们发现 CCN1 在 apoE 小鼠动脉粥样硬化主动脉中的泡沫巨噬细胞中表达明显。在 apoE 小鼠中，CCN1 处理加重了高脂血症、全身炎症和动脉粥样硬化的进展。此外，CCN1 降低了逆胆固醇转运的能力，并下调了动脉粥样硬化主动脉中 ATP 结合盒转运体 A1（ABCA1）和 ABCG1 的蛋白表达。值得注意的是，CCN1 降低了胆固醇清除相关蛋白的蛋白表达，包括肝脏中的 ABCG5、ABCG8、肝 X 受体 α（LXRα）、胆固醇 7α-水解酶和 LDL 受体，并加剧了肝脏脂质堆积。在巨噬细胞中，oxLDL 处理增加了 CCN1 的表达。用中和抗体或小干扰 RNA 抑制 CCN1 活性减弱了 oxLDL 诱导的脂质堆积。相反，CCN1 共处理或过表达 CCN1 通过下调 LXRα 依赖性 ABCA1 和 ABCG1 的表达，损害了载脂蛋白 AI 和高密度脂蛋白依赖性胆固醇流出，从而加剧了 oxLDL 诱导的脂质堆积。
我们的研究结果表明，CCN1 在调节胆固醇代谢和动脉粥样硬化的发生发展中起着关键作用。
