ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death
ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death
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ApoC2 缺乏引起严重的高甘油三酯血症和自发性动脉粥样硬化：从新生儿死亡中拯救出来的啮齿动物模型
DOI：
10.1016/j.metabol.2020.154296
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发表时间：
2020-08-01
影响因子：
9.8
通讯作者：
Xian, Xunde
中科院分区：
文献类型：
--
作者：
Gao, Mingming;Yang, Chun;Xian, Xunde
原理：ApoC 2是脂蛋白脂肪酶介导的富含磷脂酰肌醇的血浆脂蛋白水解的重要激活剂。ApoC 2缺陷型患者表现出重度高脂血症（sHTG）和复发性急性胰腺炎。然而，由于ApoC 2缺失小鼠的胚胎致死性，对ApoC 2功能的广泛了解在哺乳动物物种中受到限制。目的：我们应该在具有某些类似人类特征的啮齿动物中产生ApoC 2缺陷的动物模型，然后研究ApoC 2对脂质和葡萄糖稳态的精确影响。利用CRISPR/Cas9，我们从金黄色叙利亚仓鼠中删除Apoc 2基因，纯合（-/-）幼崽可以在足月出生，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，ApoC 2（-/-）幼仔可存活至断奶，并在成年期表现出严重的HTG。出生时单次静脉注射AAV-hApoC 2也可挽救ApoC 2（-/-）幼仔的新生儿死亡。成年ApoC 2（-/-）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。ApoC 2（-/-）成年仓鼠的sHTG不能被各种降脂药物纠正，但可被中链甘油三酯饮食部分改善，并被AAV-hApoC 2完全纠正。结论：我们的研究提供了一种新的ApoC 2缺失的严重高脂血症的大鼠模型，该模型具有充分的特征，并为治疗ApoC 2缺陷患者提供了一种潜在的治疗方法。(c)2020爱思唯尔公司All rights reserved.
Rationale: 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 deletedmouse extensive understanding of ApoC2 function is limited in mammalian species.Objective: Wesought to generate an animal modelwith ApoC2 deficiency in a rodentwith some human-like features and then study the precise effects of ApoC2 on lipid and glucose homeostasis.Methods and results: Using CRISPR/Cas9, we deleted Apoc2 gene fromgolden 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 ApoC2(-/-) hamsters 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.Conclusions: Our study provides a novel ApoC2-deletedmammalianmodelwith severe hypertriglyceridemia that was fully characterized and highlights a potential therapeutic approach for the treatment of ApoC2 deficient patients. (c) 2020 Elsevier Inc. All rights reserved.