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

详细信息    查看全文

• 作者：Cassandra K. Hayne ; Michael J. Lafferty ; Brian J. Eglinger ; John P. Kane ; Saskia B. Neher
• 刊名：Biochemistry
• 出版年：2017
• 出版时间：January 24, 2017
• 年：2017
• 卷：56
• 期：3
• 页码：525-533
• 全文大小：402K
• ISSN：1520-4995

文摘

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 serum lipid profile more favorable than that of 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 that of 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 did. An LPL structural model suggests that the LPL^S447X truncation exposes residues implicated in LPL binding to uptake receptors.