Apolipoprotein CI causes hypertriglyceridemia independent of the very-low-density lipoprotein receptor and apolipoprotein CIII in mice

Wehaverecently shownthatthepredominant hypertriglyceridemiain humanapolipoprotein C1(APOC1)transgenic miceismainlyexplainedby apoCI-mediated inhibition of the lipoprotein lipase (LPL)-dependent triglyceride (TG)-hydrolysis pathway. Since the very-low-density lipoprotein receptor (VLDLr) and apoCIII are potent modifiers of LPL activity, our current aim was to study whether the lipolysis-inhibiting action of apoCI would be dependent on the presence of the VLDLr and apoCIII in vivo. Hereto, we employed liver-specific expression of human apoCI by using a novel recombinant adenovirus (AdAPOC1). In wild-type mice, moderate apoCI expression leading to plasma human apoCI levels of 12–33 mg/dl dose-dependently and specifically increased plasma TG (up to 6.6-fold, Pb0.001), yielding the same hypertriglyceridemic phenotype as observed in humanAPOC1transgenic mice.AdAPOC1stillincreased plasmaTGinvldlr �/� mice (4.1-fold,Pb0.001)andinapoc3 �/� mice(6.8-fold,Pb0.001) that were also deficient for the low-density lipoprotein receptor (LDLr) and LDLr-related protein (LRP) or apoE, respectively. Thus, irrespective of receptor-mediatedremnant clearancebytheliver,liver-specificexpressionofhumanapoCIcauseshypertriglyceridemia intheabsenceoftheVLDLr and apoCIII. We conclude that apoCI is a powerful and direct inhibitor of LPL activity independent of the VLDLr and apoCIII.