Biochemical Analysis of the LPL Truncation Variant, LPLS447X Reveals Increased Lipoprotein Uptake

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 S447X , causes a gain-of-function. This mutation truncates two amino acids from LPL's C-terminus. Carriers of LPL S447X have decreased VLDL levels and increased HDL levels, a cardioprotective phenotype. LPL S447X is used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. It is unclear why LPL S447X results in a more favorable serum lipid profile than LPL. In vitro reports vary as to whether LPL S447X is more active than LPL. We report a comprehensive, biochemical comparison of purified LPL S447X 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 i for ANGPTL4 inhibition of LPL S447X relative to LPL. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPL S447X enhanced lipoprotein uptake to a greater degree than LPL. An LPL structural model suggests that the LPL S447X truncation exposes residues implicated in LPL binding to uptake receptors.