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

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 very-low-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 ?mol/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.

SUBMITTER: Sakurai T

PROVIDER: S-EPMC4727155 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Sakurai Toshihiro T Sakurai Akiko A Vaisman Boris L BL Amar Marcelo J MJ Liu Chengyu C Gordon Scott M SM Drake Steven K SK Pryor Milton M Sampson Maureen L ML Yang Ling L Freeman Lita A LA Remaley Alan T AT

The Journal of pharmacology and experimental therapeutics 20151116 2

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 de ...[more]

PMID: 26574515

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Project description:The emergence of pandrug-resistant bacteria breaks through the last line of defense and raises fear among people of incurable infections. In the post-antibiotic era, the pharmaceutical field turns to seek non-conventional anti-infective agents. Antimicrobial peptides are considered a prospective solution to the crisis of antimicrobial resistance. In this study, we evaluated the antimicrobial efficiency of an ApoE mimetic peptide, COG1410, which has been confirmed to exhibit strong neural protective activity and immunomodulatory function. COG1410 showed potent antimicrobial activity against pandrug-resistant Acinetobacter baumannii, even eliminating large inocula (108 CFU/ml) within 30 min. LC99.9 in PBS and 50% pooled human plasma was 2 μg/ml (1.4 μM) and 8 μg/ml (5.6 μM), respectively. Moreover, COG1410 exhibited biofilm inhibition and eradication activity, excellent stability in human plasma, and a low propensity to induce resistance. Although COG1410 easily entered bacterial cytoplasm and bound to DNA nonspecifically, the major mechanism of COG1410 killing was to disrupt the integrity of cell membrane and lead to leakage of cytoplasmic contents, without causing obvious pores on the cell surface or cell lysis. Additionally, transcriptome analysis showed that treatment with COG1410-enriched genes involved a series of oxidation–reduction processes. DCFH-DA probe detected an increased ROS level in the presence of COG1410, indicating ROS was another hit of this AMP. Furthermore, the action of COG1410 did not depend on the electronic interaction with the LPS layer, in contrast to polymyxin B. The strong synergistic interaction between COG1410 and polymyxin B dramatically reduced the working concentration of COG1410, expanding the safety window of the application. C. elegans infection model showed that combined therapy of COG1410 and polymyxin B was capable of significantly rescuing the infected nematodes. Taken together, our study demonstrates that COG1410 is a promising drug candidate in the battle against pandrug-resistant A. baumannii.

Dataset Information

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

Publications

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

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