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

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

doi:10.1016/j.metabol.2020.154296

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

Metabolism. 2020 Aug:109:154296. doi: 10.1016/j.metabol.2020.154296. Epub 2020 Jun 17.

Authors

Mingming Gao¹, Chun Yang², Xiaowei Wang³, Mengmeng Guo², Liu Yang⁴, Shanshan Gao⁴, Xin Zhang⁵, Guiyun Ruan⁶, Xiangping Li⁶, Wenhong Tian⁷, Guotao Lu⁸, Xiaoyan Dong⁷, Sisi Ma⁷, Weiqin Li⁸, Yuhui Wang², Haibo Zhu⁴, Jiuming He⁴, Hongyuan Yang⁹, George Liu¹⁰, Xunde Xian¹¹

Affiliations

¹ 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.
² Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China.
³ Laboratory of Lipid Metabolism, Institute of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
⁴ 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.
⁵ Hebei Invivo Biotech Co, Shijiazhuang, China.
⁶ Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
⁷ Beijing FivePlus Molecular Medicine Institute Co. Ltd., Beijing, China.
⁸ Surgical Intensive Care Unit, Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
⁹ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia.
¹⁰ Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China. Electronic address: [email protected].
¹¹ Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China. Electronic address: [email protected].

PMID: 32562799
DOI: 10.1016/j.metabol.2020.154296

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.

Keywords: Apolipoprotein C2; CRISPR/Cas9; Golden Syrian hamster; Hypertriglyceridemia; Lipoprotein lipase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Apolipoprotein C-II
Blood Glucose
Lipids