Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPL S447X , Reveals Increased Lipoprotein Uptake

• Published in: Biochemistry (Easton) 2017-01, Vol.56 (3), p.525-533
• Main Authors: Hayne, Cassandra K, Lafferty, Michael J, Eglinger, Brian J, Kane, John P, Neher, Saskia B
• Format: Article
• Language: English
• Subjects: Angiopoietin-like 4 Protein; Angiopoietins - chemistry; Angiopoietins - genetics; Angiopoietins - metabolism; Animals; Biological Transport; Cholesterol, HDL - chemistry; Cholesterol, HDL - metabolism; Cholesterol, LDL - chemistry; Cholesterol, LDL - metabolism; Cholesterol, VLDL - chemistry; Cholesterol, VLDL - metabolism; Gene Expression; Humans; Hyperlipidemias - blood; Hyperlipidemias - genetics; Hyperlipidemias - pathology; Lipoprotein Lipase - chemistry; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; Mice; Models, Molecular; Mutation; Protein Binding; Protein Domains; Protein Multimerization; Protein Structure, Secondary; Receptors, Lipoprotein - chemistry; Receptors, Lipoprotein - genetics; Receptors, Lipoprotein - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Serine - chemistry; Serine - metabolism; Substrate Specificity; Triglycerides - chemistry; Triglycerides - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.6b00945

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, LPL , causes a gain of function. This mutation truncates two amino acids from LPL's C-terminus. Carriers of LPL have decreased VLDL levels and increased HDL levels, a cardioprotective phenotype. LPL is used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. It is unclear why LPL results in a serum lipid profile more favorable than that of LPL. In vitro reports vary as to whether LPL is more active than LPL. We report a comprehensive, biochemical comparison of purified LPL and LPL dimers. We found no difference in specific activity on synthetic and natural substrates. We also did not observe a difference in the K for ANGPTL4 inhibition of LPL relative to that of LPL. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPL enhanced lipoprotein uptake to a greater degree than LPL did. An LPL structural model suggests that the LPL truncation exposes residues implicated in LPL binding to uptake receptors.