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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.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2020 Mar 06; Vol. 295 (10), pp. 2900-2912. Date of Electronic Publication: 2019 Oct 23. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© 2020 Nimonkar et al.)
- Subjects :
- Amino Acid Sequence
Angiopoietin-Like Protein 3
Angiopoietin-Like Protein 4 chemistry
Angiopoietin-Like Protein 4 metabolism
Angiopoietin-like Proteins chemistry
Angiopoietin-like Proteins metabolism
Animals
Binding Sites
Disease Models, Animal
Enzyme Replacement Therapy
Humans
Hyperlipoproteinemia Type I drug therapy
Hyperlipoproteinemia Type I pathology
Infusions, Subcutaneous
Lipoprotein Lipase chemistry
Lipoprotein Lipase genetics
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Protein Aggregates drug effects
Protein Stability
Receptors, Lipoprotein chemistry
Receptors, Lipoprotein genetics
Recombinant Fusion Proteins biosynthesis
Recombinant Fusion Proteins pharmacology
Recombinant Fusion Proteins therapeutic use
Lipoprotein Lipase metabolism
Receptors, Lipoprotein metabolism
Triglycerides blood
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 295
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 31645434
- Full Text :
- https://doi.org/10.1074/jbc.RA119.011079