ABCA1
ABCG1公司
泡沫电池
胆固醇逆向转运
载脂蛋白E
肝X受体
下调和上调
低密度脂蛋白受体
脂蛋白
内科学
载脂蛋白B
内分泌学
胰岛素抵抗
胆固醇
生物
化学
炎症
细胞生物学
发病机制
动脉硬化
脂质代谢
生物化学
运输机
转录因子
医学
核受体
基因
疾病
作者
Jin Feng Zhao,Hsiang Ying Chen,Jeng Wei,Shr Jeng Jim Leu,Tzong Shyuan Lee
摘要
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.
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