title: Adenovirus-mediated gene transfer of human lipoprotein lipase ameliorates the hyperlipidemias associated with apolipoprotein E and LDL receptor deficiencies in mice.
abstract: Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglyceride-rich lipoproteins. We tested the efficacy of adenovirus-mediated gene transfer of LPL as treatment of experimental hyperlipidemias associated with apolipoprotein (apoE) deficiency (apoE-/-) and low-density lipoprotein receptor (LDLr) deficiency (LDLr-/-) in mice. Replication-defective adenovirus containing the human LPL cDNA driven by a cytomegalovirus promoter (Ad.hLPL) efficiently transduced CHO-ldlA7 cells in vitro, inducing in these cells the production of bioactive LPL (73 mU/ml). Intravenous injection of Ad.hLPL (2 x 10(9) pfu) led 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 apoE-/-, LDLr-/-, and wild-type (WT) mice, respectively. Fast protein liquid chromatography (FPLC) fractionation of plasma lipoproteins showed a marked decrease in very-low-density lipoprotein (VLDL)/chylomicron remnant cholesterol (V/CR-C) in apoE-/- (83%), LDLr-/- (84%), and WT mice (58%, p < 0.01). VLDL/chylomicron remnant triglycerides (V/CR-Tg) were virtually eliminated in apoE-/- (92%), LDLr-/- (86%), and WT mice (84%, 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. Adenovirus-mediated LPL gene transfer to the liver is an effective means of reversing many of the lipoprotein abnormalities in apoE- and LDLr-deficient mice.
authors.affiliation: Baylor College of Medicine, Department of Cell Biology, Houston, TX 77030, USA.
authors.forename: E
authors.initials: E
authors.lastname: Zsigmond
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: K W
authors.initials: KW
authors.lastname: Tzung
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Fuke
authors.forename: L
authors.initials: L
authors.lastname: Chan
mesh_terms: D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000097:blood; D002914:Chylomicrons / Q000097:blood; D006224:Cricetinae; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000628:therapy*; D007275:Injections, Intravenous; D008071:Lipoprotein Lipase / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D018110:Receptors, Lipoprotein / Q000172:deficiency* / Q000235:genetics; D011994:Recombinant Proteins; D014280:Triglycerides / Q000097:blood
chemical_list: D002914:Chylomicrons; D008074:Lipoproteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D014280:Triglycerides; D006493:Heparin; D002784:Cholesterol; D008071:Lipoprotein Lipase