Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Cilpa-Karhu, Geraldine; Jauhiainen, Matti; Riekkola, Marja‐Liisa

doi:10.1194/jlr.m054288

Cited by 27 publications

(52 citation statements)

References 37 publications

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“…As a result, the N-terminal distal domain of CETP has less binding affinity to the flat surface lipid plane of polyhedral VLDLs than to the curved surface of spherical HDL. This hypothesis is consistent with the hydrophobic distal end of the N-terminal β-barrel domain of CETP interacting with HDL surface lipids and initializing CE uptake from the HDL core, as suggested by molecular dynamics simulations ( 21 , 44 , 51 ). It is also consistent with the observation that most CETPs in plasma bind to HDLs instead of VLDLs, which is due to the lower surface curvature (less hydrophobicity) of VLDLs, although the surface lipids of VLDLs are the same as those of HDLs.…”

Section: Discussionsupporting

confidence: 86%

“…Because the N-terminal β-barrel domain of CETP facilities the hydrophobic interactions with surface lipids for initializing CE uptake ( 21 , 44 , 51 ), we predicted the LDL surface could have more binding affinity to the N-terminal β-barrel domain of CETP that is between its binding affinities for HDL and VLDL because of the partially flat surface and partially curved surface revealed by the cryo-EM studies ( 25 , 52 – 55 ). The intermediate level of binding affinities between HDL and VLDL may explain how CETP can transfer CE from HDL to LDL and from LDL to VLDL.…”

Section: Discussionmentioning

confidence: 99%

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Polyhedral 3D structure of human plasma very low density lipoproteins by individual particle cryo-electron tomography1

Kuang²,

Lei

et al. 2016

Journal of Lipid Research

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Human VLDLs assembled in the liver and secreted into the circulation supply energy to peripheral tissues. VLDL lipolysis yields atherogenic LDLs and VLDL remnants that strongly correlate with CVD. Although the composition of VLDL particles has been well-characterized, their 3D structure is elusive because of their variations in size, heterogeneity in composition, structural flexibility, and mobility in solution. Here, we employed cryo-electron microscopy and individual-particle electron tomography to study the 3D structure of individual VLDL particles (without averaging) at both below and above their lipid phase transition temperatures. The 3D reconstructions of VLDL and VLDL bound to antibodies revealed an unexpected polyhedral shape, in contrast to the generally accepted model of a spherical emulsion-like particle. The smaller curvature of surface lipids compared with HDL may also reduce surface hydrophobicity, resulting in lower binding affinity to the hydrophobic distal end of the N-terminal β-barrel domain of cholesteryl ester transfer protein (CETP) compared with HDL. The directional binding of CETP to HDL and VLDL may explain the function of CETP in transferring TGs and cholesteryl esters between these particles. This first visualization of the 3D structure of VLDL could improve our understanding of the role of VLDL in atherogenesis.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Polyhedral 3D structure of human plasma very low density lipoproteins by individual particle cryo-electron tomography1

Kuang²,

Lei

et al. 2016

Journal of Lipid Research

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“… 26 Several reports on CETP inhibitors have suggested a putative mechanism for CETP inhibition on the basis of competitive interactions with CETP and HDL. 27 , 28 …”

Section: Discussionmentioning

confidence: 99%

Anti-Aging and Tissue Regeneration Ability of Policosanol Along with Lipid-Lowering Effect in Hyperlipidemic Zebrafish via Enhancement of High-Density Lipoprotein Functionality

Lee

Yoo

Lim

et al. 2016

Rejuvenation Research

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We investigated the tissue regeneration and lipid-lowering effects of policosanol (PCO) by employing a hyperlipidemic zebrafish model. A reconstituted high-density lipoprotein containing policosanol (PCO-rHDL) facilitated greater cell growth and replication with less apoptosis and reactive oxygen species (ROS) production in BV-2 microglial cell lines. From in vivo study, injection of rHDL containing apolipoprotein A-I (ApoA-I) caused 76 ± 4% (p = 0.01) greater tissue regeneration activity than the phosphate-buffered saline (PBS) control, whereas PCO-rHDL caused 94 ± 7% (p = 0.002) increased regeneration. PCO in ethanol (EtOH) showed lower cholesteryl ester transfer protein (CETP) inhibitory ability than did anacetrapib, whereas PCO-rHDL showed higher inhibitory ability than anacetrapib, suggesting a synergistic effect between PCO and rHDL. Following 9 weeks of PCO consumption, the PCO group (0.003% PCO in Tetrabit) showed the highest survivability (80%), whereas normal diet (ND) and high-cholesterol diet (HCD) control groups showed 67% and 70% survival rates, respectively. Supplementation with a HCD resulted in two-fold elevation of CETP activity along with 3- and 2.5-fold increases in serum total cholesterol (TC) and triglycerides (TGs) levels, respectively. Consumption of PCO for 9 weeks resulted in 40 ± 5% (p = 0.01 vs. HCD) and 33 ± 4% (p = 0.02 vs. HCD) reduction of TC and TGs levels, respectively. Serum high-density lipoprotein cholesterol (HDL-C) level increased up to 37 ± 2 mg/dL (p = 0.004), whereas the percentage of HDL-C/TC increased up to 20 ± 2% from 5 ± 1% compared to the HCD control. The serum glucose level was reduced to 47 ± 2% (p = 0.002) compared to the HCD control. Fatty liver change and hepatic inflammation levels were remarkably increased upon HCD consumption and were two-fold higher than that under ND. However, the PCO group showed 58 ± 5% (p = 0.001) and 50 ± 3% (p = 0.006) reduction of inflammation enzyme levels and lipid content in hepatic tissue under HCD. In conclusion, PCO supplementation showed lipid-lowering and HDL-C-elevating effects with ameliorating fatty liver change. These in vivo anti-atherosclerotic and anti-diabetic effects of PCO are well associated with in vitro anti-apoptotic activities.

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“…Recent electron microscopy (EM) studies have shown the presence of a ternary complex among CETP, HDL, and LDL/VLDL ( 16 ) in which the CETP N-terminal distal end interacts with HDL via a hydrophobic interaction ( 17 ). Independently, molecular dynamics (MD) simulations have revealed that the CETP distal ends are structurally flexible ( 18 ), and the N-terminal end penetrates into the HDL surface and takes up a CE molecule ( 19 ). A tunnel mechanism has been proposed because the CETP crystal structure displays a long hydrophobic central cavity containing two CE molecules ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations

Lei

Rames

Zhang

et al. 2016

Journal of Biological Chemistry

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Cholesteryl ester transfer protein (CETP) mediates cholesteryl ester (CE) transfer from the atheroprotective high density lipoprotein (HDL) cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy (EM) experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.

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Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Cited by 27 publications

References 37 publications

Polyhedral 3D structure of human plasma very low density lipoproteins by individual particle cryo-electron tomography1

Polyhedral 3D structure of human plasma very low density lipoproteins by individual particle cryo-electron tomography1

Anti-Aging and Tissue Regeneration Ability of Policosanol Along with Lipid-Lowering Effect in Hyperlipidemic Zebrafish via Enhancement of High-Density Lipoprotein Functionality

Insights into the Tunnel Mechanism of Cholesteryl Ester Transfer Protein through All-atom Molecular Dynamics Simulations

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