To investigate the role of LPL in mediating the clearance of lipoproteins (Lps) independent of its lipolytic function in vivo, we used recombinant adenovirus (rAdV) to express wild type LPL (LPL-WT), catalytically inactive LPL (LPL132) and luciferase (Lucif) in apoE-ko mice (n=5,7,5) and HL-ko mice (n=5,6,8). Day 4 after rAdV infusion (1-3x108 pfu) similar expression of LPL and LPL132(~4375+/-881 ng/ml)were detected in apoE- and HL-ko mice. LPL activity in mice expressing LPL-WT(~2859+/-837 nm/ml/m) was increased 3-4 fold compared to LPL132 and Lucif. Following rAdV infusion apoE-ko/LPL-WT decreased(p<0.05;all)TC(-36%), TG(-69%) and nonHDL-C(-43%) while apoE-ko/LPL132 decreased(p<0.02;all) TC(-31%), nonHDL-C(-32%) but increased TG(+213%) compared to baseline apoE-ko (mg/dl): TC=634+/-63, TG=169+/-44, nonHDL-C=620+/-64. HL-ko/LPL-WT decreased (p<0.01;all) TC(-40%), TG(-52%), PL(-33%),HDL-C(-49%) and HL-ko/LPL132 decreased (p<0.01;all) TC(-39%), HDL-C(-45%) but increased G(+200%) compared to baseline in HL-ko (mg/dl): TC=259?17, TG=111?15, PL=361?20, HDL=230?18. In both mouse models LPL132 was associated with VLDL as detected by immunoblotting of FPLC fractions and its expression led to the development of transient chylomicronemia despite NL endogenous mouse LPL activity. Thus, AdV-mediated expression of catalytically inactive LPL132,like active LPL, decreased TC(~33%)and nonHDL-C(~36%)in apoE-ko and decreased TC(~39%) and HDL-C(~47%)in HL-ko mice consistent with a non-lipolytic role of LPL in Lp metabolism. Association of LPL132 with VLDL leads to transient chylomicronemia suggesting displacement of endogeneous mLPL and emphasizes the importance of LPL-Lp interaction for lipolysis in vivo. Our studies provide new in vivo data supporting a ligand-binding role of LPL in remnant-Lp and HDL metabolism, independent of its classic function as a lipase.
