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Cited by 25Lipid metabolism and disordersLipid metabolism and biosynthesisLipoproteins and Cardiovascular Health

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

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Hayne, Cassandra K., Lafferty, Michael J., Eglinger, Brian J., Kane, John P., Neher, Saskia B.·2017·Biochemistry
DOI 10.1021/acs.biochem.6b00945PMC PMC5848218
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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, 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.

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  • The S447X mutation removes residues in the C-terminal tail of LPL, exposing a receptor-binding region that contributes to increased LPL-mediated endocytosis.

    “In vitro and modeling studies suggest that the S447X mutation removes residues in the C-terminal tail of LPL, exposing a receptor-binding region that contributes to increased LPL-mediated endocytosis [28,29].”

    From Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation (2021) · cites this paper as [29]

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Authors
Hayne, C. K., Lafferty, M. J., Eglinger, B. J., Kane, J. P., & Neher, S. B.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • University of California San Francisco Medical Center (US)
Corresponding author
Neher, Saskia B.
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2017-01-09
Volume
56
Issue
3
Pages
525-533
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/acs.biochem.6b00945
PMC
PMC5848218
OpenAlex
W2565906942
Cited by
25
References
0
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 5 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 4
FWCI
1.65
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (1 R01 HL125654)
  • American Heart Association (14BGIA20370000)
  • Division of Graduate Education (DGE-11144081)
  • Graduate School, University of North Carolina
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
lipoprotein lipase, gain-of-function mutations, lipoprotein uptake, enzyme specific activity, gene therapy, VLDL, HDL cholesterol, protein structure model
MeSH terms
Protein Domains, Angiopoietin-Like Protein 4, Animals, Biological Transport, Humans, Hyperlipidemias, Lipoprotein Lipase, Cholesterol, HDL, Cholesterol, LDL, Models, Molecular, Mutation, Protein Binding, Recombinant Proteins, Serine, Substrate Specificity, Triglycerides, Cholesterol, VLDL, Gene Expression, Protein Structure, Secondary, Receptors, Lipoprotein, Angiopoietins, Mice, Protein Multimerization

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