J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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Originally published In Press as doi:10.1194/jlr.M700281-JLR200 on December 3, 2007

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Journal of Lipid Research, Vol. 49, 572-580, March 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice

Lisa Nelbach*, Xiao Shu*,{dagger}, Robert J. Konrad§, Robert O. Ryan*,{dagger} and Trudy M. Forte1,*

* Center for Prevention of Obesity, Diabetes, and Cardiovascular Disease, Children's Hospital Oakland Research Institute, Oakland, CA 94609
{dagger} Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720
§ Eli Lilly Research Laboratories, Indianapolis, IN 46285

Published, JLR Papers in Press, December 3, 2007.

1 To whom correspondence should be addressed. e-mail: tforte{at}chori.org

Transgenic (Tg) mice that overexpress the human apolipoprotein A-V gene (APOA5) yet lack an endogenous mouse apoa5 gene (APOA5 Tg mice) were generated. Subsequently, the effect of human apoA-V expression on plasma triglyceride (TG) concentration and lipoprotein and apolipoprotein distribution was determined and compared with that in mice deficient in apoA-V (apoa5–/– mice). NMR analysis of plasma lipoproteins revealed that APOA5 Tg mice had a very low VLDL concentration (26.4 ± 7.7 nmol/dl), whereas VLDL in apoa5–/– mice was 18- fold higher (467 ± 152 nmol/dl). SDS-PAGE analysis of the d < 1.063 g/ml plasma fraction revealed that the apoB-100/apoB-48 ratio was 14-fold higher in APOA5 Tg versus apoa5–/– mice and that the apoE/total apoB ratio was 7-fold greater in APOA5 Tg versus apoa5–/– mice. It is anticipated that a reduction in apoB-100/apoB-48 ratio as well as that for apoE/apoB would impair the uptake of VLDL and remnants in apoa5–/– mice, thereby contributing to increased plasma TG levels. The concentration of apoA-V in APOA5 Tg mice was 12.5 ± 2.9 µg/ml, which is ~50- to 100-fold higher than that reported for normolipidemic humans. ApoA-V was predominantly associated with HDL but was rapidly and efficiently redistributed to apoA- V-deficient VLDL upon incubation. Consistent with findings reported for human subjects, apoA-V concentration was positively correlated with TG levels in normolipidemic APOA5 Tg mice. It is conceivable that, in a situation in which apoA-V is chronically overexpressed, complex interactions among factors regulating TG homeostasis may result in a positive correlation of apoA-V with TG concentrations.

Supplementary key words nuclear magnetic resonance • redistribution of apolipoprotein A-V • human apolipoprotein A-V transgenic mouse • apolipoprotein A-V knockout mouse • apolipoprotein A-V enzyme-linked immunosorbent assay • apolipoprotein B-100 • apolipoprotein E

Abbreviations: apoA-V, apolipoprotein A-V; apoa5–/–, apolipoprotein A-V-deficient; IDL, intermediate density lipoprotein; PVDF, polyvinylidene difluoride; Tg, transgenic; TG, triglyceride






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