ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.
ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 10(8) plaqueforming units/mouse) dose-dependently reduced plasma very low density lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the lipoprotein lipase (LPL)-dependent clearance of TG-rich lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich lipoproteins.
Schaap
Frank G
FG
AMC Liver Center, Meibergdreef 69-71, 1105 BK Amsterdam, The Netherlands. f.g.schaap@amc.uva.nl
Rensen
Patrick C N
PC
Voshol
Peter J
PJ
Vrins
Carlos
C
van der Vliet
Hendrik N
HN
Chamuleau
Robert A F M
RA
Havekes
Louis M
LM
Groen
Albert K
AK
van Dijk
Ko Willems
KW
D000256:Adenoviridae / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D006868:Hydrolysis; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D019518:Postprandial Period; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism*
C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D011994:Recombinant Proteins; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D008071:Lipoprotein Lipase