title: 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 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.
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sakurai
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Boris L
authors.initials: BL
authors.lastname: Vaisman
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Gordon
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Drake
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Milton
authors.initials: M
authors.lastname: Pryor
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Maureen L
authors.initials: ML
authors.lastname: Sampson
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland.
authors.forename: Lita A
authors.initials: LA
authors.lastname: Freeman
authors.affiliation: 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., A.T.R.), Critical Care Medicine Department, Clinical Center (S.K.D.), and Laboratory of Obesity and Metabolic Diseases, National Heart, Lung, and Blood Institute (L.Y.), National Institutes of Health, Bethesda, Maryland aremaley1@cc.nih.gov.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053304:Apolipoprotein C-II / Q000235:genetics*; D040761:Biomimetic Materials / Q000378:metabolism*; D005260:Female; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000235:genetics*; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics*; D011247:Pregnancy; D014280:Triglycerides / Q000097:blood
chemical_list: D053304:Apolipoprotein C-II; D010446:Peptide Fragments; D014280:Triglycerides