Creation of apolipoprotein C-II (ApoC-II) mutant mice and correction of their hypertriglyceridemia with an ApoC-II mimetic peptides

Toshihiro Sakurai, Akiko Sakurai, Boris L. Vaisman, Marcelo J. Amar, Chengyu Liu, Scott M. Gordon, Steven K. Drake, Milton Pryor, Maureen L. Sampson, Ling Yang, Lita A. Freeman, Alan T. Remaley

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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 verylow- density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 mmol/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.

Original languageEnglish
Pages (from-to)341-353
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume356
Issue number2
DOIs
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
The authors thank the Proteomics Core Facility of the National Heart, Lung, and Blood Institute for help on LC-MS/MS. The authors also thank the Electron Microscopy Core Facility of the National Heart, Lung, and Blood Institute for help on electron microscopy.

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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