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Lipids, Lipoproteins, and Cardiovascular Risk Factors |
1 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
2 Linco Diagnostic Services, St. Charles, MO.
aAddress correspondence to this author at: Eli Lilly Corporate Center, Building 88-358C, Indianapolis, IN 46285. Fax 317-276-5281; e-mail konrad_robert{at}lilly.com.
Background: The recently discovered apolipoprotein A5 (ApoA5) is fast gaining attention as a key regulator of serum triglyceride concentrations. An ApoA5 mouse knock-out model produced an approximately fourfold increase in serum triglycerides, whereas a knock-in model with human ApoA5 produced 50–70% lower concentrations of mouse serum triglycerides. In addition, peroxisome proliferator-activated receptor-
agonists, which are used clinically to lower serum triglyceride concentrations, cause increased ApoA5 mRNA expression. Despite these compelling molecular biology data, relatively little is known about ApoA5 protein in human serum.
Methods: To better understand circulating concentrations and lipoprotein particle distribution of ApoA5, we expressed the recombinant human ApoA5 protein and raised antibodies against both the NH2 and COOH termini.
Results: Using the above reagents, we demonstrate for the first time that ApoA5 is present in human serum, although at much lower concentrations than other apolipoproteins such as ApoA1. Using a dual-antibody sandwich ELISA that we developed, we observed ApoA5 concentrations in human serum ranging from 24 to 406 µg/L compared with 
1 g/L for ApoA1. We also examined the lipoprotein particle distribution of ApoA5 and found that ApoA5 was detectable in VLDL, HDL, and chylomicrons, but not LDL.
Conclusions: These data demonstrate for the first time that ApoA5 is a secreted protein present in human serum and is associated with specific lipoprotein particles. In addition, our data indicate that the circulating concentration of human ApoA5 is very low compared with other apolipoproteins.
The following articles in journals at HighWire Press have cited this article:
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  K. Wong-Mauldin, V. Raussens, T. M. Forte, and R. O. Ryan Apolipoprotein A-V N-terminal Domain Lipid Interaction Properties in Vitro Explain the Hypertriglyceridemic Phenotype Associated with Natural Truncation Mutants J. Biol. Chem., November 27, 2009; 284(48): 33369 - 33376. [Abstract] [Full Text] [PDF]
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 S. F. C. Vaessen, G. M. Dallinga-Thie, C. J. D. Ross, L. J. Splint, L. W. Castellani, P. C. N. Rensen, M. R. Hayden, F. G. Schaap, and J. A. Kuivenhoven Plasma apolipoprotein AV levels in mice are positively associated with plasma triglyceride levels J. Lipid Res., May 1, 2009; 50(5): 880 - 884. [Abstract] [Full Text] [PDF]
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T. M. Forte, X. Shu, and R. O. Ryan The ins (cell) and outs (plasma) of apolipoprotein A-V J. Lipid Res., April 1, 2009; 50(Supplement): S150 - S155. [Abstract] [Full Text] [PDF]
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 B. Dorfmeister, W.W. Zeng, A. Dichlberger, S.K. Nilsson, F.G. Schaap, J.A. Hubacek, M. Merkel, J.A. Cooper, A. Lookene, W. Putt, et al. Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1866 - 1871. [Abstract] [Full Text] [PDF]
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X. Shu, R. O. Ryan, and T. M. Forte Intracellular lipid droplet targeting by apolipoprotein A-V requires the carboxyl-terminal segment J. Lipid Res., August 1, 2008; 49(8): 1670 - 1676. [Abstract] [Full Text] [PDF]
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L. Nelbach, X. Shu, R. J. Konrad, R. O. Ryan, and T. M. Forte Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice J. Lipid Res., March 1, 2008; 49(3): 572 - 580. [Abstract] [Full Text] [PDF]
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I. Sundl, M. Guardiola, G. Khoschsorur, R. Sola, J. C. Vallve, G. Godas, L. Masana, M. Maritschnegg, A. Meinitzer, N. Cardinault, et al. Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene 1131T>C variant and associations with plasma lipids and lipid peroxidation J. Lipid Res., November 1, 2007; 48(11): 2506 - 2513. [Abstract] [Full Text] [PDF]
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 J. Kahri, J. Fruchart-Najib, N. Matikainen, J.-C. Fruchart, J. Vakkilainen, and M.-R. Taskinen The Increase of Apolipoprotein A-V During Postprandial Lipemia Parallels the Response of Triglyceride-Rich Lipoproteins in Type 2 Diabetes: No relationship between apoA-V and postheparin plasma lipolytic activity Diabetes Care, August 1, 2007; 30(8): 2083 - 2085. [Full Text] [PDF]
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A. Dichlberger, L. A. Cogburn, J. Nimpf, and W. J. Schneider Avian apolipoprotein A-V binds to LDL receptor gene family members J. Lipid Res., July 1, 2007; 48(7): 1451 - 1456. [Abstract] [Full Text] [PDF]
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S. Qu, G. Perdomo, D. Su, F. M. D'Souza, N. S. Shachter, and H. H. Dong Effects of apoA-V on HDL and VLDL metabolism in APOC3 transgenic mice J. Lipid Res., July 1, 2007; 48(7): 1476 - 1487. [Abstract] [Full Text] [PDF]
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X. Shu, J. Chan, R. O. Ryan, and T. M. Forte Apolipoprotein A-V association with intracellular lipid droplets J. Lipid Res., July 1, 2007; 48(7): 1445 - 1450. [Abstract] [Full Text] [PDF]
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C.-Q. Lai, D. K. Arnett, D. Corella, R. J. Straka, M. Y. Tsai, J. M. Peacock, X. Adiconis, L. D. Parnell, J. E. Hixson, M. A. Province, et al. Fenofibrate Effect on Triglyceride and Postprandial Response of Apolipoprotein A5 Variants: The GOLDN Study Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1417 - 1425. [Abstract] [Full Text] [PDF]
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J. A. Beckstead, K. Wong, V. Gupta, C.-P. L. Wan, V. R. Cook, R. B. Weinberg, P. M. M. Weers, and R. O. Ryan The C Terminus of Apolipoprotein A-V Modulates Lipid-binding Activity J. Biol. Chem., May 25, 2007; 282(21): 15484 - 15489. [Abstract] [Full Text] [PDF]
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N. Tentolouris, A. Stylianou, E. Lourida, D. Perrea, D. Kyriaki, E. C. Papavasiliou, A. D. Tselepis, and N. Katsilambros High postprandial triglyceridemia in patients with type 2 diabetes and microalbuminuria J. Lipid Res., January 1, 2007; 48(1): 218 - 225. [Abstract] [Full Text] [PDF]
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F. G. Schaap, M. C. Nierman, J. F. P. Berbee, H. Hattori, P. J. Talmud, S. F. C. Vaessen, P. C. N. Rensen, R. A. F. M. Chamuleau, J. A. Kuivenhoven, and A. K. Groen Evidence for a complex relationship between apoA-V and apoC-III in patients with severe hypertriglyceridemia J. Lipid Res., October 1, 2006; 47(10): 2333 - 2339. [Abstract] [Full Text] [PDF]
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S. F. C. Vaessen, F. G. Schaap, J.-A. Kuivenhoven, A. K. Groen, B. A. Hutten, S. M. Boekholdt, H. Hattori, M. S. Sandhu, S. A. Bingham, R. Luben, et al. Apolipoprotein A-V, triglycerides and risk of coronary artery disease: the prospective Epic-Norfolk Population Study J. Lipid Res., September 1, 2006; 47(9): 2064 - 2070. [Abstract] [Full Text] [PDF]
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 W. E. Alborn, M. G. Johnson, M. J. Prince, and R. J. Konrad Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein a5 in human serum. Clin. Chem., March 1, 2006; 52(3): 514 - 517. [Abstract] [Full Text] [PDF]
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D. C. Chan, G. F. Watts, M. N. Nguyen, and P. H. R. Barrett Apolipoproteins C-III and A-V as Predictors of Very-Low-Density Lipoprotein Triglyceride and Apolipoprotein B-100 Kinetics Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 590 - 596. [Abstract] [Full Text] [PDF]
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E. A. Ruiz-Narvaez, Y. Yang, Y. Nakanishi, J. Kirchdorfer, and H. Campos APOC3/A5 haplotypes, lipid levels, and risk of myocardial infarction in the Central Valley of Costa Rica J. Lipid Res., December 1, 2005; 46(12): 2605 - 2613. [Abstract] [Full Text] [PDF]
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P. C.N. Rensen, K. W. van Dijk, and L. M. Havekes Apolipoprotein AV: Low Concentration, High Impact Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2445 - 2447. [Full Text] [PDF]
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M. Ishihara, T. Kujiraoka, T. Iwasaki, M. Nagano, M. Takano, J. Ishii, M. Tsuji, H. Ide, I. P. Miller, N. E. Miller, et al. A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration J. Lipid Res., September 1, 2005; 46(9): 2015 - 2022. [Abstract] [Full Text] [PDF]
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A. E. Schultze, W. E. Alborn, R. K. Newton, and R. J. Konrad Administration of a PPAR{alpha} agonist increases serum apolipoprotein A-V levels and the apolipoprotein A-V/apolipoprotein C-III ratio J. Lipid Res., August 1, 2005; 46(8): 1591 - 1595. [Abstract] [Full Text] [PDF]
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M. Merkel, B. Loeffler, M. Kluger, N. Fabig, G. Geppert, L. A. Pennacchio, A. Laatsch, and J. Heeren Apolipoprotein AV Accelerates Plasma Hydrolysis of Triglyceriderich Lipoproteins by Interaction with Proteoglycan-bound Lipoprotein Lipase J. Biol. Chem., June 3, 2005; 280(22): 21553 - 21560. [Abstract] [Full Text] [PDF]
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S.-O. Olofsson ApoA-V: The Regulation of a Regulator of Plasma Triglycerides Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1097 - 1099. [Full Text] [PDF]
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V. Charlton-Menys and P. N. Durrington Apolipoprotein A5 and Hypertriglyceridemia Clin. Chem., February 1, 2005; 51(2): 295 - 297. [Full Text] [PDF]
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