Cholesteryl ester diffusion, location and self-association constraints determine CETP activity with discoidal HDL: Excimer probe study

Dergunov, Alexander D.; Shabrova, Elena; Dobretsov, G. E.

doi:10.1016/j.abb.2014.09.019

Cited by 8 publications

(8 citation statements)

References 56 publications

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“…However, our results are inconsistent with those of other investigators who have shown that CETP binds to the edge of discoidal HDL35 via an interaction with apoA-I36, and atomistic and coarse-grained simulations of CETP–HDL interaction which have shown that the N-terminus helix-X domain of CETP penetrates deeply into the HDL particle core37. Nonetheless, our results favor a tunnel, not a shuttle mechanism whereby CETP no longer binds to HDL when it has acquired an appropriate number of CEs from HDL.…”

Section: Discussioncontrasting

confidence: 99%

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Zhang

Charles

Tong

et al. 2015

Sci Rep

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Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol esters (CE) from atheroprotective high-density lipoproteins (HDL) to atherogenic low-density lipoproteins (LDL). CETP inhibition has been regarded as a promising strategy for increasing HDL levels and subsequently reducing the risk of cardiovascular diseases (CVD). Although the crystal structure of CETP is known, little is known regarding how CETP binds to HDL. Here, we investigated how various HDL-like particles interact with CETP by electron microscopy and molecular dynamics simulations. Results showed that CETP binds to HDL via hydrophobic interactions rather than protein-protein interactions. The HDL surface lipid curvature generates a hydrophobic environment, leading to CETP hydrophobic distal end interaction. This interaction is independent of other HDL components, such as apolipoproteins, cholesteryl esters and triglycerides. Thus, disrupting these hydrophobic interactions could be a new therapeutic strategy for attenuating the interaction of CETP with HDL.

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Section: Discussioncontrasting

confidence: 99%

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

Zhang

Charles

Tong

et al. 2015

Sci Rep

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“…Recently, Dergunov et al reported experimentally measured values of 0.17−0.33 × 10 −7 cm 2 s −1 for the lateral diffusion coefficient for a cholesteryl 1-pyrenedecanoate (CPD) probe in reconstituted HDL particles. 35 This value is in agreement with our result for unlabeled CE. Also, there are some important similarities between our unlabeled CE and the CPD probe.…”

Section: Free Energy Calculations Show Different Localization Of Unla...supporting

confidence: 93%

“…Recently, this has been done with a cholesteryl 1pyrenedecanoate probe in reconstituted discoidal HDL particles. 35 To our knowledge, the behavior of esterified BOPIPY-labeled cholesterol in lipoproteins has not yet been characterized. However, access to an effective and wellcharacterized fluorescent CE analogue would be paramount for efforts to study cholesterol transport.…”

Section: Introductionmentioning

confidence: 99%

“…In order to study cholesterol transport in a lipoprotein environment, it is important to label also the esterified form of cholesterol. Recently, this has been done with a cholesteryl 1-pyrenedecanoate probe in reconstituted discoidal HDL particles . To our knowledge, the behavior of esterified BOPIPY-labeled cholesterol in lipoproteins has not yet been characterized.…”

Section: Introductionmentioning

confidence: 99%

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How Well Does BODIPY-Cholesteryl Ester Mimic Unlabeled Cholesteryl Esters in High Density Lipoprotein Particles?

2015

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We compare the behavior of unlabeled and BODIPY-labeled cholesteryl ester (CE) in high density lipoprotein by atomistic molecular dynamics simulations. We find through replica exchange umbrella sampling and unbiased molecular dynamics simulations that BODIPY labeling has no significant effect on the partitioning of CE between HDL and the water phase. However, BODIPY-CE was observed to diffuse more slowly and locate itself closer to the HDL-water interface than CE due to the BODIPY probe that is constrained to the surface region, and because the CE body in BODIPY-CE prefers to align itself away from the HDL surface. The implications as to the suitability of BODIPY to explore lipoprotein properties are discussed.

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“…From a mathematical point of view, solution for this system requires knowledge of all the parameters, initial concentrations of all the components and kinetic parameters, which are given in Table 3 , Table 4 , Table 5 and Table 6 and calculated based on data from [ 1 , 25 , 45 , 46 , 47 , 48 , 49 , 50 ]. The system was solved using the MATLAB software package over reaction time of up to 3 h which was chosen to compare modelling results with experimentally obtained data [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

Mathematical Modelling of Material Transfer to High-Density Lipoprotein (HDL) upon Triglyceride Lipolysis by Lipoprotein Lipase: Relevance to Cardioprotective Role of HDL

Schekatolina¹,

Lahovska²,

Bekshaev

et al. 2022

Metabolites

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High-density lipoprotein (HDL) contributes to lipolysis of triglyceride-rich lipoprotein (TGRL) by lipoprotein lipase (LPL) via acquirement of surface lipids, including free cholesterol (FC), released upon lipolysis. According to the reverse remnant-cholesterol transport (RRT) hypothesis recently developed by us, acquirement of FC by HDL is reduced at both low and extremely high HDL concentrations, potentially underlying the U-shaped relationship between HDL-cholesterol and cardiovascular disease. Mechanisms underlying impaired FC transfer however remain indeterminate. We developed a mathematical model of material transfer to HDL upon TGRL lipolysis by LPL. Consistent with experimental observations, mathematical modelling showed that surface components of TGRL, including FC, were accumulated in HDL upon lipolysis. The modelling successfully reproduced major features of cholesterol accumulation in HDL observed experimentally, notably saturation of this process over time and appearance of a maximum as a function of HDL concentration. The calculations suggested that the both phenomena resulted from competitive fluxes of FC through the HDL pool, including primarily those driven by FC concentration gradient between TGRL and HDL on the one hand and mediated by lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) on the other hand. These findings provide novel opportunities to revisit our view of HDL in the framework of RRT.

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Cholesteryl ester diffusion, location and self-association constraints determine CETP activity with discoidal HDL: Excimer probe study

Cited by 8 publications

References 56 publications

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation

How Well Does BODIPY-Cholesteryl Ester Mimic Unlabeled Cholesteryl Esters in High Density Lipoprotein Particles?

Mathematical Modelling of Material Transfer to High-Density Lipoprotein (HDL) upon Triglyceride Lipolysis by Lipoprotein Lipase: Relevance to Cardioprotective Role of HDL

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