Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China; Laboratory of Lipid Metabolism, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China.
Metabolism. 2020 Aug;109:154296. doi: 10.1016/j.metabol.2020.154296. Epub 2020 Jun 17.
ApoC2 is an important activator for lipoprotein lipase-mediated hydrolysis of triglyceride-rich plasma lipoproteins. ApoC2-deficient patients display severe hypertriglyceridemia (sHTG) and recurrent acute pancreatitis. However, due to embryonic lethality in ApoC2 deleted mouse extensive understanding of ApoC2 function is limited in mammalian species.
We sought to generate an animal model with ApoC2 deficiency in a rodent with some human-like features and then study the precise effects of ApoC2 on lipid and glucose homeostasis.
Using CRISPR/Cas9, we deleted Apoc2 gene from golden Syrian hamster and the homozygous (-/-) pups can be born in matured term but exhibited neonatal lethality. By continuous iv administration of normal hamster serum the ApoC2 pups could survive till weaning and displayed severe HTG in adulthood on chow diet. A single iv injection of AAV-hApoC2 at birth can also rescue the neonatal death of ApoC2 pups. Adult ApoC2hamsters exhibited a unique phenotype of sHTG with hypoglycemia, hypoinsulinemia and spontaneous atherosclerosis. The sHTG in ApoC2 adult hamsters could not be corrected by various lipid-lowering medications, but partially ameliorated by medium chain triglyceride diet and completely corrected by AAV-hApoC2.
Our study provides a novel ApoC2-deleted mammalian model with severe hypertriglyceridemia that was fully characterized and highlights a potential therapeutic approach for the treatment of ApoC2 deficient patients.
载脂蛋白 C2（ApoC2）是脂蛋白脂肪酶介导水解富含甘油三酯的血浆脂蛋白的重要激活剂。载脂蛋白 C2 缺乏症患者表现出严重的高甘油三酯血症（sHTG）和复发性急性胰腺炎。然而，由于载脂蛋白 C2 缺失的小鼠具有胚胎致死性，因此在哺乳动物中对载脂蛋白 C2 功能的广泛了解受到限制。
我们试图在具有某些人类特征的啮齿动物中生成载脂蛋白 C2 缺乏的动物模型，然后研究载脂蛋白 C2 对脂质和葡萄糖稳态的精确影响。
使用 CRISPR/Cas9，我们从金黄地鼠中删除了 Apoc2 基因，纯合子（-/-）幼崽可以足月出生，但表现出新生儿致死性。通过连续静脉内给予正常仓鼠血清，ApoC2 幼崽可以存活到断奶，并在成年期在普通饮食上表现出严重的 HTG。出生时单次静脉内注射 AAV-hApoC2 也可以挽救 ApoC2 幼崽的新生儿死亡。成年 ApoC2 仓鼠表现出独特的 sHTG 表型，伴有低血糖、低胰岛素血症和自发性动脉粥样硬化。各种降脂药物不能纠正 ApoC2 成年仓鼠的 sHTG，但中链甘油三酯饮食部分改善，AAV-hApoC2 完全纠正。
我们的研究提供了一种新型的严重高甘油三酯血症的载脂蛋白 C2 缺失哺乳动物模型，并充分描述了该模型，强调了治疗载脂蛋白 C2 缺乏症患者的潜在治疗方法。
