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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | 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. |
Description | Author Affiliation: Sakurai T ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Sakurai A ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Vaisman BL ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Amar MJ ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Liu C ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Gordon SM ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Drake SK ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Pryor M ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Sampson ML ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Yang L ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Freeman LA ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,); Remaley AT ( Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute (T.S., A.S., B.L.V., M.J.A., C.L., S.M.G., M.P., L.A.F., A.T.R.), Transgenic Core Facility, National Heart, Lung, and Blood Institute (C.L.), Department of Laboratory Medicine, Clinical Center (M.L.S.,) |
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 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. |
File Format | HTM / HTML |
ISSN | 00223565 |
e-ISSN | 15210103 |
DOI | 10.1124/jpet.115.229740 |
Journal | Journal of Pharmacology and Experimental Therapeutics |
Issue Number | 2 |
Volume Number | 356 |
Language | English |
Publisher | American Society for Pharmacology and Experimental Therapeutics |
Publisher Date | 2016-02-01 |
Publisher Place | United States |
Access Restriction | Open |
Subject Keyword | Apolipoprotein C-ii Amino Acid Sequence Peptide Fragments Mice, Inbred C57bl Molecular Sequence Data Research Support, N.i.h., Intramural Biomimetic Materials Triglycerides Metabolism Discipline Pharmacology Hyperlipoproteinemia Type I Blood Pregnancy Animals Discipline Therapeutics Hypertriglyceridemia Genetics Mice Mutation |
Content Type | Text |
Resource Type | Article |
Subject | Pharmacology Molecular Medicine |
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