Abstract 430: Efficacy of ApoC-II Mimetic Peptide in Novel Apoc2 Mutant Mice With Hypertriglyceridemia and Impaired Insulin Sensitivity

Abstract

Apolipoprotein C-II (apoC-II) is a cofactor for activating lipoprotein lipase, which hydrolyzes triglycerides (TGs). ApoC-II deficiency causes hypertriglyceridemia in humans. Here, we created Apoc2 mutant mice by using zinc finger nucleases and characterized the mice on lipid and glucose metabolism. We also investigated the efficacy of C-II-a, an apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice had apoC-II with an uncleaved signal peptide that strongly binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had elevated plasma TG (757.5 ± 281.2 mg/dL) derived from very-low density lipoprotein and chylomicron remnants (40-200 nm) and low HDL cholesterol (31.4 ± 14.7 mg/dL) compared with wild-type mice (TG, 55.9 ± 13.3 mg/dL; HDL cholesterol, 55.9 ± 14.3 mg/dL). The homozygous mice had significantly increased body weight and % fat mass (36.4 g; 26.0% at 6-mon-old) compared to wild-type mice (29.6 g; 17.5%). Less movement and much heat (Energy expenditure) in homozygous mice was observed by metabolic cage. Both Glucose and insulin tolerance tests also revealed insulin resistance in homozygous mice. Intravenous injection of C-II-a (0.2, 1, and 5 μmol/kg body weight) decreased plasma TG in a dose-dependent manner, with a maximum reduction of 90% at 30 minutes after the high dose. TG did not return to baseline until 2 days later. Subcutaneous or intramuscular injections also had similar effects. Plasma half-life of C-II-a was 1.33 ± 0.72 hours, suggesting that C-II-a only acutely supports activation of lipolysis, and the sustained TG reduction is due to the relatively slow synthesis of TG-rich lipoproteins. Additionally, insulin tolerance test in both wild-type and homozygous mice showed improvement tendency of insulin sensitivity in intraperitoneal injections of C-II-a (1 μmol/kg) five times for 9 days. In conclusion, we found a novel mouse model of apoC-II deficiency with insulin resistance and obesity as well as hypertriglyceridemia and also revealed apoC-II mimetic peptide can ameliorate hypertriglyceridemia and insulin resistance in the mice, could be a potential new therapy for apoC-II deficiency and insulin resistance.