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A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome

Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological...

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Autores principales: Nimonkar, Amitabh V., Weldon, Stephen, Godbout, Kevin, Panza, Darrell, Hanrahan, Susan, Cubbon, Rose, Xu, Fangmin, Trauger, John W., Gao, Jiaping, Voznesensky, Andrei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062184/
https://www.ncbi.nlm.nih.gov/pubmed/31645434
http://dx.doi.org/10.1074/jbc.RA119.011079
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author Nimonkar, Amitabh V.
Weldon, Stephen
Godbout, Kevin
Panza, Darrell
Hanrahan, Susan
Cubbon, Rose
Xu, Fangmin
Trauger, John W.
Gao, Jiaping
Voznesensky, Andrei
author_facet Nimonkar, Amitabh V.
Weldon, Stephen
Godbout, Kevin
Panza, Darrell
Hanrahan, Susan
Cubbon, Rose
Xu, Fangmin
Trauger, John W.
Gao, Jiaping
Voznesensky, Andrei
author_sort Nimonkar, Amitabh V.
collection PubMed
description Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL–GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL–GPIHBP1 fusion protein exhibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL–GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS.
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spelling pubmed-70621842020-03-16 A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome Nimonkar, Amitabh V. Weldon, Stephen Godbout, Kevin Panza, Darrell Hanrahan, Susan Cubbon, Rose Xu, Fangmin Trauger, John W. Gao, Jiaping Voznesensky, Andrei J Biol Chem Editors' Picks Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL–GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL–GPIHBP1 fusion protein exhibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL–GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS. American Society for Biochemistry and Molecular Biology 2020-03-06 2019-10-23 /pmc/articles/PMC7062184/ /pubmed/31645434 http://dx.doi.org/10.1074/jbc.RA119.011079 Text en © 2020 Nimonkar et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Editors' Picks
Nimonkar, Amitabh V.
Weldon, Stephen
Godbout, Kevin
Panza, Darrell
Hanrahan, Susan
Cubbon, Rose
Xu, Fangmin
Trauger, John W.
Gao, Jiaping
Voznesensky, Andrei
A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome
title A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome
title_full A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome
title_fullStr A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome
title_full_unstemmed A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome
title_short A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome
title_sort lipoprotein lipase–gpi-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: implications for managing familial chylomicronemia syndrome
topic Editors' Picks
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062184/
https://www.ncbi.nlm.nih.gov/pubmed/31645434
http://dx.doi.org/10.1074/jbc.RA119.011079
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