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...
محفوظ في:
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| مؤلفون آخرون: | , |
| منشور في: |
2023
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إضافة وسم
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| الملخص: | <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> |
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