title: Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5.
abstract: 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.
authors.affiliation: 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
authors.forename: Jamila
authors.initials: J
authors.lastname: Fruchart-Najib
authors.forename: Eric
authors.initials: E
authors.lastname: Baugé
authors.forename: Loredan-Stefan
authors.initials: LS
authors.lastname: Niculescu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pham
authors.forename: Benoit
authors.initials: B
authors.lastname: Thomas
authors.forename: Corinne
authors.initials: C
authors.lastname: Rommens
authors.forename: Zouher
authors.initials: Z
authors.lastname: Majd
authors.forename: Bryan
authors.initials: B
authors.lastname: Brewer
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
mesh_terms: 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*
chemical_list: 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