Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.
Overexpression of human APOA5 in mice results in dramatically decreased plasma triglyceride levels. In this study we explored the mechanism underlying this hypotriglyceridemic effect. Initially we found that triglyceride turnover was faster in hAPOA5 transgenic mice compared to controls, and this strongly correlated with increased LPL activity in postheparin plasma. Furthermore, we show that in vitro recombinant apoAV interacts physically with lipoprotein lipase and significantly increased its activity. We show that both apoB and apoCIII are decreased in hAPOA5 transgenic mice indicating a decrease in VLDL number. To further investigate the mechanism of hAPOA5 in a hyperlipidemic background, we inter-crossed hAPOA5 and hAPOC3 transgenic mice. We found a marked decrease in VLDL triglyceride and cholesterol, as well as apolipoprotein B and CIII levels. These data indicated that apoAV induces a decrease in VLDL size by activating lipolysis and an increase of VLDL clearance. In a postprandial state, the normal triglyceride response found in wild-type mice was significantly reduced in hAPOA5 transgenics. In addition, we demonstrated that in response to this fat load in hAPOA5xhAPOC3 mice, apoAV, but not apoCIII, was redistributed from primarily HDL to VLDL. This shift of apoAV in VLDL appears to limit the increase of triglyceride by activating the lipoprotein lipase.
Fruchart-Najib
Jamila
J
Département d'Athérosclérose, UR 545 INSERM, Institut Pasteur de Lille et Université de Lille II, 1 rue du Pr. Calmette-BP 245, 59019 Lille Cedex, France. jamila.fruchart@pasteur-lille.fr
Baugé
Eric
E
Niculescu
Loredan-Stefan
LS
Pham
Tatiana
T
Thomas
Benoit
B
Rommens
Corinne
C
Majd
Zouher
Z
Brewer
Bryan
B
Pennacchio
Len A
LA
Fruchart
Jean-Charles
JC
D000818:Animals; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A; D001055:Apolipoproteins B / Q000378:metabolism; D001056:Apolipoproteins C / Q000235:genetics / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008066:Lipolysis; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019518:Postprandial Period; D014280:Triglycerides / Q000097:blood*
C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D014280:Triglycerides; D008071:Lipoprotein Lipase