Evidence map›Paper›PMID 25387803›Full record

ArticleCirculation research2015

GPIHBP1 missense mutations often cause multimerization of GPIHBP1 and thereby prevent lipoprotein lipase binding.

Anne P Beigneux, Loren G Fong, André Bensadoun, Brandon S J Davies, Monika Oberer, Henrik Gårdsvoll, Michael Ploug, Stephen G Young

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.

0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed
4.1field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

37 citing papers in PubMed, 51 citations in OpenAlex.

  1. GPIHBP1 on oligodendrocytes binds lipoprotein lipase within the human brain.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  2. Article
  3. A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2022
    Article
  4. Article
  5. A homozygous variant in theFrontiers in genetics · 2022
    Article
  6. Article
  7. Review
  8. Review
  9. Chylomicronemia from GPIHBP1 autoantibodies.Journal of lipid research · 2020
    Review
  10. Article
  11. Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2020
    Article
  12. Review
  13. Article
  14. Review
  15. Evolution and Medical Significance of LU Domain-Containing Proteins.International journal of molecular sciences · 2019
    Review
  16. Article
  17. Article
  18. Lipoprotein lipase is active as a monomer.Proceedings of the National Academy of Sciences of the United States of America · 2019
    Article
  19. Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis.Proceedings of the National Academy of Sciences of the United States of America · 2019
    Article
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors at 1 institution in 2 countries.

Anne P BeigneuxFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles. abeigneux@mednet.ucla.edu.
Loren G FongFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
André BensadounFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
Brandon S J DaviesFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
Monika ObererFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
Henrik GårdsvollFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
Michael PlougFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
Stephen G YoungFrom the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles (A.P.B., L.G.F., S.G.Y.); Division of Nutritional Science, Cornell University, Ithaca, NY (A.B.); Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City (B.S.J.D.); Institute of Molecular Biosciences, University of Graz, Graz, Austria (M.O.); Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (H.G., M.P.); and Molecular Biology Institute (S.G.Y.), Department of Human Genetics, David Geffen School of Medicine (S.G.Y.), University of California at Los Angeles.
University of Copenhagen · DK

Funding

The Lipin Protein Family and Triglyceride Metabolism P01HL090553 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI YOUNG, STEPHEN G. · 2008 to 2018
$23.3M
Refining Physiologic Mechanisms for Intravascular Triglyceride MetabolismR01HL087228 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI BEIGNEUX, ANNE, FONG, LOREN GI · 2007 to 2024
$7.8M
New Avenues in GPIHBP1 ResearchR01HL094732 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI BEIGNEUX, ANNE · 2009 to 2012
$1.8M
NHLBI NIH HHS HL087228NHLBI NIH HHS HL090553NHLBI NIH HHS HL094732NHLBI NIH HHS P01 HL090553NHLBI NIH HHS R01 HL087228NHLBI NIH HHS R01 HL094732
6 · The paper itself

Abstract

rationaleGPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) in the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1 missense mutations that interfere with LPL binding cause familial chylomicronemia.

objectiveWe sought to understand mechanisms by which GPIHBP1 mutations prevent LPL binding and lead to chylomicronemia. METHODS AND

resultsWe expressed mutant forms of GPIHBP1 in Chinese hamster ovary cells, rat and human endothelial cells, and Drosophila S2 cells. In each expression system, mutation of cysteines in GPIHBP1's Ly6 domain (including mutants identified in patients with chylomicronemia) led to the formation of disulfide-linked dimers and multimers. GPIHBP1 dimerization/multimerization was not unique to cysteine mutations; mutations in other amino acid residues, including several associated with chylomicronemia, also led to protein dimerization/multimerization. The loss of GPIHBP1 monomers is relevant to the pathogenesis of chylomicronemia because only GPIHBP1 monomers-and not dimers or multimers-are capable of binding LPL. One GPIHBP1 mutant, GPIHBP1-W109S, had distinctive properties. GPIHBP1-W109S lacked the ability to bind LPL but had a reduced propensity for forming dimers or multimers, suggesting that W109 might play a more direct role in binding LPL. In support of that idea, replacing W109 with any of 8 other amino acids abolished LPL binding-and often did so without promoting the formation of dimers and multimers.

conclusionsMany amino acid substitutions in GPIHBP1's Ly6 domain that abolish LPL binding lead to protein dimerization/multimerization. Dimerization/multimerization is relevant to disease pathogenesis, given that only GPIHBP1 monomers are capable of binding LPL.

Indexed as

Mutation, MissenseAnimalsBinding SitesCHO CellsCricetulusCysteineDrosophilaHumansHuman Umbilical Vein Endothelial CellsHyperlipoproteinemia Type ILipoprotein LipaseModels, MolecularPhosphoinositide Phospholipase CProtein BindingProtein ConformationProtein MultimerizationCysteineGPIHBP1 protein, humanGPI-HBP1 protein, mouseLipoprotein LipaseLPL protein, humanPhosphoinositide Phospholipase CReceptors, Lipoproteinchylomicronsendothelial cellsGPIHBP1 proteinhypertriglyceridemialipoprotein lipaseprotein multimerizationtriglycerides

Identifiers

PMID25387803
PMCPMC4329087
OpenAlexW2120437898

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.