Efficacy Of Apoc-Ii Mimetic Peptide In Novel Apoc2 Mutant Mice With Hypertriglyceridemia And Impaired Insulin Sensitivity

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...