ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglycerides (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis
article
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 3.1.1.34; Lipoproteins; Lipoproteins, VLDL; Recombinant Proteins; Triglycerides; very low density lipoprotein triglyceride
Topics
Biomedical ResearchData reductionEnzymesGene transferMetabolismReaction kineticsLipolytic conversionLipoproteinsBiochemistryApolipoprotein AApolipoprotein a5TriacylglycerolUnclassified drugVery low density lipoproteinAnimal experimentAPO5 geneGeneGene transferHydrolysisHyperlipidemiaHypertriglyceridemiaLipid blood levelLipid metabolismLipoprotein blood levelMouseNonhumanTriacylglycerol blood levelAdenoviridaeAdipose TissueAnimalsApolipoproteinsDose-Response Relationship, DrugGene Transfer TechniquesHydrolysisKineticsLipidsLipoprotein LipaseLipoproteinsLipoproteins, VLDLLiverMaleMiceMice, Inbred C57BLMuscle, SkeletalPostprandial PeriodRatsRecombinant ProteinsTime FactorsTriglyceridesAnimaliaMurinae
TNO Identifier
237899
ISSN
00219258
Source
Journal of Biological Chemistry, 279(27), pp. 27941-27947.
Pages
27941-27947