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

Abstract

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.

• Authors: Mingming Gao, Chun Yang, Xiaowei Wang, Mengmeng Guo, Liu Yang, Shanshan Gao, Xin Zhang, Guiyun Ruan, Xiangping Li, Wenhong Tian, Guotao Lu, Xiaoyan Dong, Sisi Ma, Weiqin Li, Yuhui Wang, Haibo Zhu, Jiuming He, Hongyuan Yang, George Liu, Xunde Xian
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 109 Pg. 154296 (08 2020) ISSN: 1532-8600 [Electronic] United States
• PMID: 32562799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Apolipoprotein C-II
• Blood Glucose
• Lipids

Topics

• Animals
• Animals, Newborn (genetics)
• Apolipoprotein C-II (deficiency, therapeutic use)
• Atherosclerosis (etiology)
• Blood Glucose
• Cricetinae
• Disease Models, Animal
• Gene Knockout Techniques
• Homeostasis
• Humans
• Hypertriglyceridemia (drug therapy, etiology)
• Lipids
• Mesocricetus