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. 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: georgeliu@bjmu.edu.cn. 11. Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University, Beijing, China. Electronic address: xianxunde@bjmu.edu.cn.
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.
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.