ADENOVIRUS-MEDIATED GENE-TRANSFER OF HUMAN LIPOPROTEIN-LIPASE AMELIORATES THE HYPERLIPIDEMIAS ASSOCIATED WITH APOLIPOPROTEIN-E AND LDL RECEPTOR DEFICIENCIES IN MICE

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysi s of triglyceride-rich lipoproteins. We tested the efficacy of adenovi rus-mediated gene transfer of LPL as treatment of experimental hyperli pidemias associated with apolipoprotein (apoE) deficiency (apoE-/-) an d low-density lipoprotein receptor (LDLr) deficiency (LDLr-/-) in mice . Replication-defective adenovirus containing the human LPL cDNA drive n by a cytomegalovirus promoter (Ad.hLPL) efficiently transduced CHO-l dlA7 cells in vitro, inducing in these cells the production of bioacti ve LPL (73 mU/ml). Intravenous injection of Ad.hLPL (2 x 10(9) pfu) le d to high-level expression of hLPL mRNA and LPL activity in the liver (88.3 mU/ml) and in post-heparin plasma (116.1 mU/ml). Overexpression of LPL resulted in marked reductions in total plasma cholesterol (TC; 48%, 43%, 25%) and triglycerides (TTg; 63%, 40%, 70%, p < 0.01) in apo E-/-, LDLr-/-, and wild-type (WT) mice, respectively. Fast protein liq uid chromatography (FPLC) fractionation of plasma lipoproteins showed a marked decrease in very-low-density lipoprotein (VLDL)/chylomicron r emnant, cholesterol (V/CR-C) in apoE-/-(83%), LDLr-/- (84%), and WT mi ce (58%, p < 0.01). VLDL/chylomicron remnant triglycerides (V/CR-Tg) w ere virtually eliminated in apoE-/-(92%), LDLr-/-(86%), and WT mice (8 4%, p < 0.05). No significant changes were detected in LPL activities, plasma lipids, or lipoproteins of mice injected with a control virus, Ad.Luc, containing the luciferase instead of the LPL cDNA. In summary , infusion of Ad.hLPL leads to increased liver and post-heparin plasma LPL activities, significantly reduced TC, TTg, V/CR-C, and V/CR-Tg in WT mice, as well as in mice with apoE and LDLr deficiencies. Adenovir us-mediated LPL gene transfer to the liver is an effective means of re versing many of the lipoprotein abnormalities in apoE- and LDLr-defici ent mice.