ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death.,Metabolism

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ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: A rodent model rescued from neonatal death.
Metabolism ( IF 9.8 ) Pub Date : 2020-06-17 , DOI: 10.1016/j.metabol.2020.154296
Mingming Gao ₁ , Chun Yang ₂ , Xiaowei Wang ₃ , Mengmeng Guo ₂ , Liu Yang ₄ , Shanshan Gao ₄ , Xin Zhang ₅ , Guiyun Ruan ₆ , Xiangping Li ₆ , Wenhong Tian ₇ , Guotao Lu ₈ , Xiaoyan Dong ₇ , Sisi Ma ₇ , Weiqin Li ₈ , Yuhui Wang ₂ , Haibo Zhu ₄ , Jiuming He ₄ , Hongyuan Yang ₉ , George Liu ₂ , Xunde Xian ₂

Affiliation

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.
Laboratory of Lipid Metabolism, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xian Nong Tan Street 1, Xicheng District, Beijing 100050, China.
Hebei Invivo Biotech Co, Shijiazhuang, China.
Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
Beijing FivePlus Molecular Medicine Institute Co. Ltd., Beijing, China.
Surgical Intensive Care Unit, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.

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 deleted mouse extensive understanding of ApoC2 function is limited in mammalian species.

Objective

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.

Methods and results

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 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-deleted mammalian model with severe hypertriglyceridemia that was fully characterized and highlights a potential therapeutic approach for the treatment of ApoC2 deficient patients.

中文翻译：

ApoC2缺乏会引起严重的高甘油三酸酯血症和自发性动脉粥样硬化：一种从新生儿死亡中救出的啮齿动物模型。

基本原理

ApoC2是脂蛋白脂肪酶介导的富含甘油三酸酯的血浆脂蛋白水解的重要激活剂。缺乏ApoC2的患者表现出严重的高甘油三酸酯血症（sHTG）和复发性急性胰腺炎。但是，由于删除了ApoC2的胚胎致死性，小鼠对ApoC2功能的广泛了解有限。

目的

我们试图在具有某些类人特征的啮齿动物中生成ApoC2缺乏症的动物模型，然后研究ApoC2对脂质和葡萄糖稳态的精确作用。

方法与结果

使用CRISPR / Cas9，我们从金色的叙利亚仓鼠中删除了Apoc2基因，纯合（-/-）幼犬可以成熟出生，但表现出新生儿致死性。通过连续静脉注射正常仓鼠血清，ApoC2 ^-/-幼仔可以生存直至断奶，并在成年饮食中表现出严重的HTG。在出生时一次静脉注射AAV-hApoC2也可以挽救ApoC2 ^-/-幼仔的新生儿死亡。成年ApoC2 ^-/-仓鼠表现出sHTG的独特表型，具有低血糖，低胰岛素血症和自发性动脉粥样硬化。ApoC2中的sHTG ^-/- 成年仓鼠无法通过各种降脂药物进行矫正，但中链甘油三酸酯饮食可以部分缓解，而AAV-hApoC2可以完全矫正。