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

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.