ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein
<h3>Background</h3><p dir="ltr">HDL possesses anti-inflammatory properties, however, the exact mechanism is not fully understood. Endotoxin is a potent inducers of TLR4 signaling, leading to inflammatory mediators’ release. It has been estimated that TLR4 recognizes about...
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2023
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| _version_ | 1864513530407944192 |
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| author | Hanaa Mousa (11645606) |
| author2 | Angelos Thanassoulas (2822861) Susu M. Zughaier (14151987) |
| author2_role | author author |
| author_facet | Hanaa Mousa (11645606) Angelos Thanassoulas (2822861) Susu M. Zughaier (14151987) |
| author_role | author |
| dc.creator.none.fl_str_mv | Hanaa Mousa (11645606) Angelos Thanassoulas (2822861) Susu M. Zughaier (14151987) |
| dc.date.none.fl_str_mv | 2023-07-01T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.bbrep.2023.101445 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/ApoM_binds_endotoxin_contributing_to_neutralization_and_clearance_by_High_Density_Lipoprotein/25018256 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Clinical sciences Chemical sciences Medicinal and biomolecular chemistry ApoM Endotoxin Isothermal calorimetry Lipopolysaccharide HDL Neutralization TNFα |
| dc.title.none.fl_str_mv | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <h3>Background</h3><p dir="ltr">HDL possesses anti-inflammatory properties, however, the exact mechanism is not fully understood. Endotoxin is a potent inducers of TLR4 signaling, leading to inflammatory mediators’ release. It has been estimated that TLR4 recognizes about 5% of circulating lipopolysaccharide whereas 95% is cleared by plasma lipoproteins, mainly HDL. ApoM is required for HDL biogenesis and 95% of plasma ApoM is found associated with HDL, both are significantly reduced during sepsis.</p><h3>Aim</h3><p dir="ltr">The aim of this study is to investigate whether ApoM binds endotoxin and contributes to anti-inflammatory activity of HDL.</p><h3>Methods</h3><p dir="ltr">Isothermal Titration Calorimetry (ITC) was used to determine the binding of ultrapure <i>E. coli</i> LPS to the recombinant ApoM protein. Purified human HDL and recombinant ApoM was used to investigate LPS neutralization using human and murine macrophages and computational simulation was performed.</p><h3>Result</h3><p dir="ltr">ApoM shows high affinity for <i>E. coli</i> LPS, forming 1:1 complexes with Kd values below 1 μΜ, as revealed by ITC. The binding process is strongly exothermic and enthalpy-driven (Δ<sub>r</sub>H = −36.5 kJ/mol), implying the formation of an extensive network of interactions between ApoM and LPS in the bound state. Computational simulation also predicted high-affinity binding between ApoM and <i>E. coli</i> LPS and the best scoring models showed <i>E. coli</i> LPS docking near the calyx of ApoM without blocking the pocket. The biological significance of this interaction was further demonstrated in macrophages where purified HDL neutralized an <i>E. coli</i> LPS effect and significantly reduced TNFα release from human THP-1 cells.</p><h3>Conclusion</h3><p dir="ltr">ApoM binds LPS to facilitate endotoxin neutralization and clearance by HDL.</p><h2>Other Information</h2><p dir="ltr">Published in: Biochemistry and Biophysics Reports<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.bbrep.2023.101445" target="_blank">https://dx.doi.org/10.1016/j.bbrep.2023.101445</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_a3f1870963c53cb087cfca3ead3e690f |
| identifier_str_mv | 10.1016/j.bbrep.2023.101445 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25018256 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | ApoM binds endotoxin contributing to neutralization and clearance by High Density LipoproteinHanaa Mousa (11645606)Angelos Thanassoulas (2822861)Susu M. Zughaier (14151987)Biological sciencesBiochemistry and cell biologyBiomedical and clinical sciencesClinical sciencesChemical sciencesMedicinal and biomolecular chemistryApoMEndotoxinIsothermal calorimetryLipopolysaccharideHDLNeutralizationTNFα<h3>Background</h3><p dir="ltr">HDL possesses anti-inflammatory properties, however, the exact mechanism is not fully understood. Endotoxin is a potent inducers of TLR4 signaling, leading to inflammatory mediators’ release. It has been estimated that TLR4 recognizes about 5% of circulating lipopolysaccharide whereas 95% is cleared by plasma lipoproteins, mainly HDL. ApoM is required for HDL biogenesis and 95% of plasma ApoM is found associated with HDL, both are significantly reduced during sepsis.</p><h3>Aim</h3><p dir="ltr">The aim of this study is to investigate whether ApoM binds endotoxin and contributes to anti-inflammatory activity of HDL.</p><h3>Methods</h3><p dir="ltr">Isothermal Titration Calorimetry (ITC) was used to determine the binding of ultrapure <i>E. coli</i> LPS to the recombinant ApoM protein. Purified human HDL and recombinant ApoM was used to investigate LPS neutralization using human and murine macrophages and computational simulation was performed.</p><h3>Result</h3><p dir="ltr">ApoM shows high affinity for <i>E. coli</i> LPS, forming 1:1 complexes with Kd values below 1 μΜ, as revealed by ITC. The binding process is strongly exothermic and enthalpy-driven (Δ<sub>r</sub>H = −36.5 kJ/mol), implying the formation of an extensive network of interactions between ApoM and LPS in the bound state. Computational simulation also predicted high-affinity binding between ApoM and <i>E. coli</i> LPS and the best scoring models showed <i>E. coli</i> LPS docking near the calyx of ApoM without blocking the pocket. The biological significance of this interaction was further demonstrated in macrophages where purified HDL neutralized an <i>E. coli</i> LPS effect and significantly reduced TNFα release from human THP-1 cells.</p><h3>Conclusion</h3><p dir="ltr">ApoM binds LPS to facilitate endotoxin neutralization and clearance by HDL.</p><h2>Other Information</h2><p dir="ltr">Published in: Biochemistry and Biophysics Reports<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.bbrep.2023.101445" target="_blank">https://dx.doi.org/10.1016/j.bbrep.2023.101445</a></p>2023-07-01T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.bbrep.2023.101445https://figshare.com/articles/journal_contribution/ApoM_binds_endotoxin_contributing_to_neutralization_and_clearance_by_High_Density_Lipoprotein/25018256CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/250182562023-07-01T00:00:00Z |
| spellingShingle | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein Hanaa Mousa (11645606) Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Clinical sciences Chemical sciences Medicinal and biomolecular chemistry ApoM Endotoxin Isothermal calorimetry Lipopolysaccharide HDL Neutralization TNFα |
| status_str | publishedVersion |
| title | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| title_full | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| title_fullStr | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| title_full_unstemmed | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| title_short | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| title_sort | ApoM binds endotoxin contributing to neutralization and clearance by High Density Lipoprotein |
| topic | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Clinical sciences Chemical sciences Medicinal and biomolecular chemistry ApoM Endotoxin Isothermal calorimetry Lipopolysaccharide HDL Neutralization TNFα |