LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia With Dominant Inheritance and Diet-induced Coronary Atherosclerosis.
LDL Receptor Gene-ablated Hamsters: A Rodent Model of Familial Hypercholesterolemia With Dominant Inheritance and Diet-induced Coronary Atherosclerosis.
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LDL 受体基因消除仓鼠：具有显性遗传和饮食诱导的冠状动脉粥样硬化的家族性高胆固醇血症的啮齿动物模型
DOI：
10.1016/j.ebiom.2017.12.013
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发表时间：
2018-01
期刊：
影响因子：
11.1
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Guo X;Gao M;Wang Y;Lin X;Yang L;Cong N;An X;Wang F;Qu K;Yu L;Wang Y;Wang J;Zhu H;Xian X;Liu G
家族性高胆固醇血症（FH）是一种常染色体显性遗传病，主要由低密度脂蛋白受体（Ldlr）基因突变引起。与 FH 患者不同，杂合 Ldlr 敲除 (KO) 小鼠不表现出显性 FH 特征。与人类一样，仓鼠也具有胆固醇酯转移蛋白、仅限肠道的 ApoB 编辑和肝脏胆固醇合成水平较低。在这里，我们使用 CRISPR/Cas9 技术生成了 Ldlr 消融仓鼠。采用饲料饮食的纯合 Ldlr KO 仓鼠会出现以 LDL 为主要脂蛋白的高胆固醇血症和自发性动脉粥样硬化。在高胆固醇/高脂肪（HCHF）饮食下，这些动物表现出严重的高脂血症以及主动脉和冠状动脉的动脉粥样硬化病变。此外，短期HCHF饮食的杂合Ldlr KO仓鼠也有明显的高胆固醇血症，几种降脂药物可以有效改善这种情况。重要的是，接受 3 个月 HCHF 饮食的杂合子会加速主动脉和冠状动脉的病变。我们的研究结果表明，Ldlr KO 仓鼠是人类 FH 的首选动物模型，在高脂血症和冠心病的转化研究中具有巨大潜力。利用CRISPR/Cas9编辑系统成功生成了Ldlr基因敲除仓鼠。丢失一份 Ldlr 基因会使仓鼠容易患上饮食引起的高脂血症和冠状动脉粥样硬化。杂合 Ldlr KO 仓鼠对不同降脂药物的反应存在差异。采用饲料饮食的纯合 Ldlr KO 仓鼠会出现严重的高胆固醇血症和自发性动脉粥样硬化。基因工程动物模型，特别是小鼠模型，已被广泛用于研究心血管疾病的发病机制。然而，小鼠和人类代谢特征的明显差异限制了小鼠模型在了解人类动脉粥样硬化方面的进一步应用。在本研究中，我们使用 CRISPR/Cas9 编辑系统删除仓鼠中的 Ldlr 基因，仓鼠是一种与人类表现出相似代谢特征的物种。饮食诱导的杂合 Ldlr KO 仓鼠表现出高脂血症，主动脉和冠状动脉均出现动脉粥样硬化病变，这种情况在 FH 患者中观察到，但在小鼠中未观察到。此外，以食物饮食的老年纯合Ldlr KO仓鼠表现出严重的高胆固醇血症和自发性动脉粥样硬化。我们的工作探索类人动物模型，用于人类动脉粥样硬化的基础和转化研究。
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease caused mainly by LDL receptor (Ldlr) gene mutations. Unlike FH patients, heterozygous Ldlr knockout (KO) mice do not show a dominant FH trait. Hamsters, like humans, have the cholesteryl ester transfer protein, intestine-only ApoB editing and low hepatic cholesterol synthesis. Here, we generated Ldlr-ablated hamsters using CRISPR/Cas9 technology. Homozygous Ldlr KO hamsters on a chow diet developed hypercholesterolemia with LDL as the dominant lipoprotein and spontaneous atherosclerosis. On a high-cholesterol/high-fat (HCHF) diet, these animals exhibited severe hyperlipidemia and atherosclerotic lesions in the aorta and coronary arteries. Moreover, the heterozygous Ldlr KO hamsters on a short-term HCHF diet also had overt hypercholesterolemia, which could be effectively ameliorated with several lipid-lowering drugs. Importantly, heterozygotes on 3-month HCHF diets developed accelerated lesions in the aortas and coronary arteries. Our findings demonstrate that the Ldlr KO hamster is an animal model of choice for human FH and has great potential in translational research of hyperlipidemia and coronary heart disease. Ldlr knockout hamsters were successfully generated by using the CRISPR/Cas9 editing system. Loss of one copy of the Ldlr gene predisposes hamsters to diet-induced hyperlipidemia and coronary atherosclerosis. Heterozygous Ldlr KO hamsters differentially respond to different lipid-lowering drugs. Homozygous Ldlr KO hamsters on a chow diet develop severe hypercholesterolemia and spontaneous atherosclerosis. Genetically engineered animal models, especially mouse models, have been widely used to study the pathogenesis of cardiovascular disease. However, distinct differences in the metabolic profiles of mice and humans limit further applications of mouse models toward understanding atherosclerosis in humans. In the present study, we use the CRISPR/Cas9 editing system to delete the Ldlr gene in hamsters, a species exhibiting similar metabolic features to those of humans. Diet-induced heterozygous Ldlr KO hamsters show hyperlipidemia with atherosclerotic lesions in both the aorta and coronary arteries, which has been observed in FH patients but not in mice. Moreover, aged homozygous Ldlr KO hamsters on a chow diet display severe hypercholesterolemia and spontaneous atherosclerosis. Our work explores a human-like animal model for basic and translational research of human atherosclerosis.
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影响因子：
5.4
作者：
Li Y;Fuchimoto D;Sudo M;Haruta H;Lin QF;Takayama T;Morita S;Nochi T;Suzuki S;Sembon S;Nakai M;Kojima M;Iwamoto M;Hashimoto M;Yoda S;Kunimoto S;Hiro T;Matsumoto T;Mitsumata M;Sugitani M;Saito S;Hirayama A;Onishi A
通讯作者：
Onishi A
影响因子：
6.5
作者：
Millar, JS;Cromley, DA;Billheimer, JT
通讯作者：
Billheimer, JT
影响因子：
5.3
作者：
Lu, Yongbin;Cheng, Zhiyuan;Cheng, Ning
通讯作者：
Cheng, Ning
影响因子：
15.9
作者：
ISHIBASHI, S;BROWN, MS;HERZ, J
通讯作者：
HERZ, J
基于指南的他汀类药物的资格，冠状动脉钙化和心血管事件。
DOI：
10.1001/jama.2015.7515
发表时间：
2015-07-14
期刊：
JAMA
影响因子：
--
作者：
Pursnani A;Massaro JM;D'Agostino RB Sr;O'Donnell CJ;Hoffmann U
通讯作者：
Hoffmann U