Effect of apolipoprotein A-V on plasma triglyceride, lipoprotein size, and composition in genetically engineered mice.
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 microg/ml, which is approximately 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.
Nelbach
Lisa
L
Center for Prevention of Obesity, Diabetes, and Cardiovascular Disease, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
Shu
Xiao
X
Konrad
Robert J
RJ
Ryan
Robert O
RO
Forte
Trudy M
TM
D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000172:deficiency; D001054:Apolipoproteins A / Q000235:genetics / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000097:blood; D008074:Lipoproteins / Q000737:chemistry* / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010316:Particle Size; D014280:Triglycerides / Q000097:blood*
C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D014280:Triglycerides