title: Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake.
abstract: Lipoprotein lipase (LPL) is responsible for the hydrolysis of triglycerides from circulating lipoproteins. Whereas most identified mutations in the LPL gene are deleterious, one mutation, LPLS447X, causes a gain of function. This mutation truncates two amino acids from LPL's C-terminus. Carriers of LPLS447Xhave decreased VLDL levels and increased HDL levels, a cardioprotective phenotype. LPLS447Xis used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. It is unclear why LPLS447Xresults in a serum lipid profile more favorable than that of LPL. In vitro reports vary as to whether LPLS447Xis more active than LPL. We report a comprehensive, biochemical comparison of purified LPLS447Xand LPL dimers. We found no difference in specific activity on synthetic and natural substrates. We also did not observe a difference in the Kifor ANGPTL4 inhibition of LPLS447Xrelative to that of LPL. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPLS447Xenhanced lipoprotein uptake to a greater degree than LPL did. An LPL structural model suggests that the LPLS447Xtruncation exposes residues implicated in LPL binding to uptake receptors.
authors.affiliation: Department Biochemistry and Biophysics, University of North Carolina at Chapel Hill , 120 Mason Farm Road, CB7260, Chapel Hill, North Carolina 27599, United States.
authors.forename: Cassandra K
authors.initials: CK
authors.lastname: Hayne
authors.affiliation: Department Biochemistry and Biophysics, University of North Carolina at Chapel Hill , 120 Mason Farm Road, CB7260, Chapel Hill, North Carolina 27599, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lafferty
authors.affiliation: Department Biochemistry and Biophysics, University of North Carolina at Chapel Hill , 120 Mason Farm Road, CB7260, Chapel Hill, North Carolina 27599, United States.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Eglinger
authors.affiliation: University of California San Francisco Medical Center , San Francisco, California 94115, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: Kane
authors.affiliation: Department Biochemistry and Biophysics, University of North Carolina at Chapel Hill , 120 Mason Farm Road, CB7260, Chapel Hill, North Carolina 27599, United States.
authors.forename: Saskia B
authors.identifier: 0000-0003-4165-6674
authors.initials: SB
authors.lastname: Neher
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D008076:Cholesterol, HDL / Q000737:chemistry* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000737:chemistry* / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics / Q000473:pathology; D008071:Lipoprotein Lipase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D018110:Receptors, Lipoprotein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D014280:Triglycerides / Q000737:chemistry* / Q000378:metabolism
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; C472779:GPI-HBP1 protein, mouse; C523701:GPIHBP1 protein, human; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D014280:Triglycerides; D012694:Serine; C548261:LPL protein, human; D008071:Lipoprotein Lipase