Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing 100191, China.
Lipid Metabolism Laboratory, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
EBioMedicine. 2018 Jan;27:214-224. doi: 10.1016/j.ebiom.2017.12.013. Epub 2017 Dec 15.
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.
家族性高胆固醇血症（FH）是一种常染色体显性遗传疾病，主要由 LDL 受体（Ldlr）基因突变引起。与 FH 患者不同，杂合子 Ldlr 基因敲除（KO）小鼠不表现出显性 FH 特征。仓鼠与人类一样，具有胆固醇酯转移蛋白、肠型 ApoB 编辑和低肝胆固醇合成。在这里，我们使用 CRISPR/Cas9 技术生成了 Ldlr 基因敲除的仓鼠。在普通饮食中，杂合子 Ldlr KO 仓鼠发生高胆固醇血症，以 LDL 为主的脂蛋白和自发性动脉粥样硬化。在高胆固醇/高脂肪（HCHF）饮食中，这些动物表现出严重的高脂血症和主动脉及冠状动脉的动脉粥样硬化病变。此外，短期 HCHF 饮食的杂合子 Ldlr KO 仓鼠也表现出明显的高胆固醇血症，几种降脂药物可有效改善。重要的是，接受 3 个月 HCHF 饮食的杂合子仓鼠在主动脉和冠状动脉的病变进展加快。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有很大的潜力。
