Biochemical Analysis of the Lipoprotein Lipase 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, LPLs447x, causes a gain of function. This mutation truncates two amino acids from LPL's C terminus. Carriers of LPLS447X have decreased VLDL levels and increased HDI., levels, a cardioprotettive phenotype. LPLS447X is used in Alipogene tiparvovec, the gene therapy product for individuals with familial LPL deficiency. It is unclear why LPLS447X results in a serum lipid profile more favorable than that of LPL. In vitro reports vary as to whether LPLS447X is more active than LPL. We report a comprehensive,-biochemical comparison of purified LPLS447X and LPL dimers. We found no difference in specific activity on synthetic substrates. We also did not observe a difference in'the Ki for ANGPTL4 inhibition of LPLS447X relative to that of LPL. Finally, we analyzed LPL-mediated uptake of fluorescently labeled lipoprotein particles and found that LPLS447X enhanced lipoprotein uptake to a greater degree than LPL did. An LPL structural model suggests that the LPLS447X truncation exposes residues implicated in LPL binding to uptake receptors.