Loss of LCAT activity in the golden Syrian hamster elicits pro-atherogenic dyslipidemia and enhanced atherosclerosis
Loss of LCAT activity in the golden Syrian hamster elicits pro-atherogenic dyslipidemia and enhanced atherosclerosis
复制标题
金色叙利亚仓鼠 LCAT 活性丧失会引发促动脉粥样硬化血脂异常并加剧动脉粥样硬化
DOI：
10.1016/j.metabol.2018.03.003
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发表时间：
2018-06-01
影响因子：
9.8
通讯作者：
Liu, George
中科院分区：
文献类型：
--
作者：
Dong, Zhao;Shi, Haozhe;Liu, George
目的：胆固醇酰基转移酶（LCAT）在高密度脂蛋白代谢中起着关键作用，但其对动脉粥样硬化的影响在动物和临床研究中仍存在争议。由于缺乏胆固醇酯转运蛋白（cholesteryl ester transfer protein，CETP）是小鼠和人类脂蛋白代谢的主要差异，我们旨在建立一种表达内源性CETP的LCAT活性缺陷的叙利亚金黄地鼠模型，以探讨其代谢特征，特别是LCAT对动脉粥样硬化发展的影响。与野生型对照动物相比，使用各种常规方法研究了突变仓鼠的脂质代谢特征和动脉粥样硬化的发展。结果：缺乏LCAT活性的仓鼠表现出促动脉粥样硬化性血脂异常，如降低高密度脂蛋白（HDL）和ApoAl，高胆固醇血症，乳糜微粒/NLDL积聚和显著增加ApoB 100/48。对高脂血症的机制研究显示，LPL介导的脂解受损，极低密度脂蛋白（VLDL）分泌增加，参与脂质合成和转运的肝脏基因上调。突变仓鼠的促动脉粥样硬化性血脂异常在高脂饮食喂养后加剧，最终导致动脉粥样硬化病变增加近3倍和5倍的主动脉en面和窦病变quantitations.Conclusions：我们的研究结果表明，LCAT缺乏在仓鼠发展促动脉粥样硬化性血脂异常，促进动脉粥样硬化病变的形成。爱思唯尔公司出版
Objective: Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in HDL metabolism but its influence on atherosclerosis remains controversial for decades both in animal and clinical studies. Because lack of cholesteryl ester transfer protein (CETP) is a major difference between murine and humans in lipoprotein metabolism, we aimed to create a novel Syrian Golden hamster model deficient in LCAT activity, which expresses endogenous CETP, to explore its metabolic features and particularly the influence of LCAT on the development of atherosclerosis.Methods: CRISPR/CAS9 gene editing system was employed to generate mutant LCAT hamsters. The characteristics of lipid metabolism and the development of atherosclerosis in the mutant hamsters were investigated using various conventional methods in comparison with wild type control animals.Results: Hamsters lacking LCAT activity exhibited pro-atherogenic dyslipidemia as diminished high density lipoprotein (HDL) and ApoAl, hypertriglyceridemia, Chylomicron/NLDL accumulation and significantly increased ApoB100/48. Mechanistic study for hypertriglyceridemia revealed impaired LPL-mediated lipolysis and increased very low density lipoprotein (VLDL) secretion, with upregulation of hepatic genes involved in lipid synthesis and transport. The pro-atherogenic dyslipidemia in mutant hamsters was exacerbated after high fat diet feeding, ultimately leading to near a 3- and 5-fold increase in atherosclerotic lesions by aortic en face and sinus lesion quantitation, respectively.Conclusions: Our findings demonstrate that LCAT deficiency in hamsters develops pro-atherogenic dyslipidemia and promotes atherosclerotic lesion formation. Published by Elsevier Inc.