Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions.
Lipoprotein lipase (LPL), a crucial enzyme in the intravascular hydrolysis of triglyceride-rich lipoproteins, is a potential drug target for the treatment of hypertriglyceridemia. The activity and stability of LPL are influenced by a complex ligand network. Previous studies performed in dilute solut...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0283358 |
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| author | Robert Risti Kathryn H Gunn Kristofer Hiis-Hommuk Natjan-Naatan Seeba Hamed Karimi Ly Villo Marko Vendelin Saskia B Neher Aivar Lõokene |
| author_facet | Robert Risti Kathryn H Gunn Kristofer Hiis-Hommuk Natjan-Naatan Seeba Hamed Karimi Ly Villo Marko Vendelin Saskia B Neher Aivar Lõokene |
| author_sort | Robert Risti |
| collection | DOAJ |
| description | Lipoprotein lipase (LPL), a crucial enzyme in the intravascular hydrolysis of triglyceride-rich lipoproteins, is a potential drug target for the treatment of hypertriglyceridemia. The activity and stability of LPL are influenced by a complex ligand network. Previous studies performed in dilute solutions suggest that LPL can appear in various oligomeric states. However, it was not known how the physiological environment, that is blood plasma, affects the action of LPL. In the current study, we demonstrate that albumin, the major protein component in blood plasma, has a significant impact on LPL stability, oligomerization, and ligand interactions. The effects induced by albumin could not solely be reproduced by the macromolecular crowding effect. Stabilization, isothermal titration calorimetry, and surface plasmon resonance studies revealed that albumin binds to LPL with affinity sufficient to form a complex in both the interstitial space and the capillaries. Negative stain transmission electron microscopy and raster image correlation spectroscopy showed that albumin, like heparin, induced reversible oligomerization of LPL. However, the albumin induced oligomers were structurally different from heparin-induced filament-like LPL oligomers. An intriguing observation was that no oligomers of either type were formed in the simultaneous presence of albumin and heparin. Our data also suggested that the oligomer formation protected LPL from the inactivation by its physiological regulator angiopoietin-like protein 4. The concentration of LPL and its environment could influence whether LPL follows irreversible inactivation and aggregation or reversible LPL oligomer formation, which might affect interactions with various ligands and drugs. In conclusion, the interplay between albumin and heparin could provide a mechanism for ensuring the dissociation of heparan sulfate-bound LPL oligomers into active LPL upon secretion into the interstitial space. |
| first_indexed | 2024-04-09T17:01:42Z |
| format | Article |
| id | doaj.art-471c224a265c4d6c8a964152aa0edf8f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-09T17:01:42Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-471c224a265c4d6c8a964152aa0edf8f2023-04-21T05:32:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01184e028335810.1371/journal.pone.0283358Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions.Robert RistiKathryn H GunnKristofer Hiis-HommukNatjan-Naatan SeebaHamed KarimiLy VilloMarko VendelinSaskia B NeherAivar LõokeneLipoprotein lipase (LPL), a crucial enzyme in the intravascular hydrolysis of triglyceride-rich lipoproteins, is a potential drug target for the treatment of hypertriglyceridemia. The activity and stability of LPL are influenced by a complex ligand network. Previous studies performed in dilute solutions suggest that LPL can appear in various oligomeric states. However, it was not known how the physiological environment, that is blood plasma, affects the action of LPL. In the current study, we demonstrate that albumin, the major protein component in blood plasma, has a significant impact on LPL stability, oligomerization, and ligand interactions. The effects induced by albumin could not solely be reproduced by the macromolecular crowding effect. Stabilization, isothermal titration calorimetry, and surface plasmon resonance studies revealed that albumin binds to LPL with affinity sufficient to form a complex in both the interstitial space and the capillaries. Negative stain transmission electron microscopy and raster image correlation spectroscopy showed that albumin, like heparin, induced reversible oligomerization of LPL. However, the albumin induced oligomers were structurally different from heparin-induced filament-like LPL oligomers. An intriguing observation was that no oligomers of either type were formed in the simultaneous presence of albumin and heparin. Our data also suggested that the oligomer formation protected LPL from the inactivation by its physiological regulator angiopoietin-like protein 4. The concentration of LPL and its environment could influence whether LPL follows irreversible inactivation and aggregation or reversible LPL oligomer formation, which might affect interactions with various ligands and drugs. In conclusion, the interplay between albumin and heparin could provide a mechanism for ensuring the dissociation of heparan sulfate-bound LPL oligomers into active LPL upon secretion into the interstitial space.https://doi.org/10.1371/journal.pone.0283358 |
| spellingShingle | Robert Risti Kathryn H Gunn Kristofer Hiis-Hommuk Natjan-Naatan Seeba Hamed Karimi Ly Villo Marko Vendelin Saskia B Neher Aivar Lõokene Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions. PLoS ONE |
| title | Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions. |
| title_full | Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions. |
| title_fullStr | Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions. |
| title_full_unstemmed | Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions. |
| title_short | Combined action of albumin and heparin regulates lipoprotein lipase oligomerization, stability, and ligand interactions. |
| title_sort | combined action of albumin and heparin regulates lipoprotein lipase oligomerization stability and ligand interactions |
| url | https://doi.org/10.1371/journal.pone.0283358 |
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