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.
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.
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 ApoC2hamsters 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.
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.
Copyright © 2020. Published by Elsevier Inc.
ApoC2 deficiency elicits severe hypertriglyceridemia and spontaneous atherosclerosis: a rodent model rescued from neonatal death.
