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ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglycerides (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis

Author: Schaap, F.G. · Rensen, P.C.N. · Voshol, P.J. · Vrins, C. · Vliet, H.N. van der · Chamuleau, R.A.F.M. · Havekes, L.M. · Groen, A.K. · Dijk, K.W. van
Institution: TNO Preventie en Gezondheid
Source:Journal of Biological Chemistry, 27, 279, 27941-27947
Identifier: 237899
doi: doi:10.1074/jbc.M403240200
Keywords: Biology · Biomedical Research · Data reduction · Enzymes · Gene transfer · Metabolism · Reaction kinetics · Lipolytic conversion · Lipoproteins · Biochemistry · Apolipoprotein A · Apolipoprotein a5 · Triacylglycerol · Unclassified drug · Very low density lipoprotein · Animal experiment · APO5 gene · Gene · Gene transfer · Hydrolysis · Hyperlipidemia · Hypertriglyceridemia · Lipid blood level · Lipid metabolism · Lipoprotein blood level · Mouse · Nonhuman · Triacylglycerol blood level · Adenoviridae · Adipose Tissue · Animals · Apolipoproteins · Dose-Response Relationship, Drug · Gene Transfer Techniques · Hydrolysis · Kinetics · Lipids · Lipoprotein Lipase · Lipoproteins · Lipoproteins, VLDL · Liver · Male · Mice · Mice, Inbred C57BL · Muscle, Skeletal · Postprandial Period · Rats · Recombinant Proteins · Time Factors · Triglycerides · Animalia · Murinae


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 108 plaque-forming 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. Chemicals / CAS: Apoa5 protein, mouse; Apolipoproteins; Lipids; Lipoprotein Lipase, EC; Lipoproteins; Lipoproteins, VLDL; Recombinant Proteins; Triglycerides; very low density lipoprotein triglyceride