Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 356; no. 2; p. 341
• Main Authors: Sakurai, Toshihiro, Sakurai, Akiko, Vaisman, Boris L, Amar, Marcelo J, Liu, Chengyu, Gordon, Scott M, Drake, Steven K, Pryor, Milton, Sampson, Maureen L, Yang, Ling, Freeman, Lita A, Remaley, Alan T
• Format: Journal Article
• Language: English
• Published: United States 01-02-2016
• Subjects: Amino Acid Sequence; Animals; Apolipoprotein C-II - genetics; Biomimetic Materials - metabolism; Female; Hyperlipoproteinemia Type I - blood; Hyperlipoproteinemia Type I - genetics; Hypertriglyceridemia - blood; Hypertriglyceridemia - genetics; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mutation - genetics; Peptide Fragments - genetics; Pregnancy; Triglycerides - blood
• ISSN: 1521-0103
• DOI: 10.1124/jpet.115.229740

Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 ± 281.2 mg/dl) 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). TGs were found in light (density < 1.063 g/ml) lipoproteins in the size range of very-low-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 μmol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 ± 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency.