Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits
Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits
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DOI：
10.1161/atvbaha.120.314368
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发表时间：
2020-08
期刊：
影响因子：
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通讯作者：
Haizhao Yan;Haizhao Yan;M. Niimi;F. Matsuhisa;Huanjin Zhou;S. Kitajima;Yajie Chen;Chuan Wang;Xiawen Yang;Jian Yao;Dongshan Yang;Jifeng Zhang;M. Murakami;K. Nakajima;Yao Wang;Enqi Liu;Jingyan Liang;Y. E. Chen;Jianglin Fan;Jianglin Fan
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文献类型：
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作者：
Haizhao Yan;Haizhao Yan;M. Niimi;F. Matsuhisa;Huanjin Zhou;S. Kitajima;Yajie Chen;Chuan Wang;Xiawen Yang;Jian Yao;Dongshan Yang;Jifeng Zhang;M. Murakami;K. Nakajima;Yao Wang;Enqi Liu;Jingyan Liang;Y. E. Chen;Jianglin Fan;Jianglin Fan
文本中提供了补充数字内容。目的：Apo（载脂蛋白）CIII 介导富含甘油三酯（TG）的脂蛋白的代谢。高水平的血浆apoCIII与血浆TG水平呈正相关，并增加心血管风险。然而，apoCIII是否直接参与动脉粥样硬化的发生发展尚未完全阐明。方法和结果：为了研究 apoCIII 在脂蛋白代谢和动脉粥样硬化中的可能作用，我们使用 ZFN（锌指核酸酶）技术生成了 apoCIII KO（敲除）兔。在正常标准饮食中，apoCIII KO 兔子的血浆 TG 水平显着低于 WT（野生型）兔子，而总胆固醇和 HDL（高密度脂蛋白）胆固醇水平没有变化。通过连续超速离心分离的脂蛋白分析表明，KO 兔血浆 TG 水平降低，同时伴随着 VLDL（极低密度脂蛋白）和 IDL（中密度脂蛋白）的显着降低。此外，KO兔在静脉注射脂肪负荷后表现出比WT兔更快的TG清除率。在富含胆固醇的饮食中，KO 兔子的血浆总胆固醇和 TG 水平持续显着低于 WT 兔子，这是由于 β-VLDL（主要致动脉粥样硬化脂蛋白）显着减少所致。与从 WT 兔中分离的 β-VLDL 相比，KO 兔的 β-VLDL 被培养的肝细胞吸收更高，并且从循环中清除得更快。与WT兔相比，KO兔的主动脉和冠状动脉粥样硬化均显着减少。结论：这些结果表明apoCIII缺陷促进富含TG的脂蛋白分解代谢，治疗性抑制apoCIII表达可能成为治疗高脂血症和动脉粥样硬化的新手段。
Supplemental Digital Content is available in the text. Objective: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of β-VLDLs—the major atherogenic lipoproteins. β-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than β-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. Conclusions: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.