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

Zhang, Meng; Charles, River; Tong, Huimin; Zhang, Lei; Patel, Mayuri; Wang, Francis; Rames, Matthew J.; Ren, Amy; Rye, Kerry‐Anne; Qiu, Xiayang; Johns, Douglas G.; Charles, M. Arthur; Ren, Gang

doi:10.1038/srep08741

Cited by 49 publications

(81 citation statements)

References 60 publications

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“…Epidemiological and clinical studies link low levels of HDL with an terminal ␤-barrel domain penetrating the lipoprotein surface [20,21]. The C-terminal domain of CETP may thus interact with HDL and LDL or VLDL, thus building a ternary complex leading to a conformational change, resulting in a hydrophobic tunnel whereby CE is transferred from HDL to lower density lipoproteins [22]. More recent findings, however, indicate that the ternary tunnel complex, ie HDL-CETP-LDL, is not a prerequisite for the transfer, since antibodies against different CETP epitopes do not interfere with the transfer of CE [23].…”

Section: Introduction: the Cetp Inhibitors Aim Of Therapeutics And Imentioning

confidence: 99%

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Ferri

Corsini

Sirtori

et al. 2018

Pharmacological Research

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Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85-0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit or if HDL-C-rise is a crucial factor still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.

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Section: Introduction: the Cetp Inhibitors Aim Of Therapeutics And Imentioning

confidence: 99%

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Ferri

Corsini

Sirtori

et al. 2018

Pharmacological Research

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“…The remnants can be further hydrolyzed to form LDLs by hepatic lipase, and the LDLs can be internalized by several mechanisms, including interaction with the LDL receptor ( 8 ). In plasma, VLDLs can also exchange their containing TGs with HDL CEs mediated by CE transfer protein (CETP) via a tunnel mechanism ( 19 – 21 ) by which the hydrophobic distal end of the N-terminal β-barrel domain dominantly interacts with HDLs via a hydrophobic interaction ( 22 ). It is unclear why this hydrophobic distal end has less interaction with the same types of surface lipids of VLDL.…”

mentioning

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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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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“…Due to the incapability of the current assays and highly heterogeneous of lipoprotein particles, the function of lipoprotein in cholesterol transport remains elusive with regard to many important questions, such as how the lipoprotein particle assembles and how the assembly modulates the neutral lipids dynamic exchanges at the molecular level. Cryo-EM coupled with MD simulations have revealed several important mechanisms of CETP-mediated lipid exchange and metabolism with all-atom detail [89,95]. Further researches could pay more attention to simultaneously monitor the dynamic structural change of lipoproteins and the dynamic mechanism of lipid transfer, especially the internal motivation of physical mechanism during the process of lipid transport.…”

Section: Resultsmentioning

confidence: 99%

Structural Basis and Functional Mechanism of Lipoprotein in Cholesterol Transport

Yang¹,

Hao²,

Che³

et al. 2018

Cholesterol - Good, Bad and the Heart

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Lipoprotein transports lipids in circulation and is primary driver/modulator of atherosclerosis. Highly dynamics of lipoprotein conformations are crucial to lipid transport along the cholesterol transport pathway, where high-density lipoprotein (HDL), lowdensity lipoprotein (LDL) and cholesteryl ester transfer protein (CETP) are major players in lipid digestion & transport and the plasma cholesterol metabolism. This chapter covered how do HDL, LDL and CETP induce the metabolisms during cholesterol transport, and summarized recent process in the spatial information of the three lipoproteins, especially the elevations of plasma HDL and LDL, and shine a light on the assembly processes of lipoprotein particles and the substrates dynamics exchanges, for an in-depth understanding on the correlation between various lipoprotein classes and cardiovascular risk.

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

Cited by 49 publications

References 60 publications

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Present therapeutic role of cholesteryl ester transfer protein inhibitors

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

Structural Basis and Functional Mechanism of Lipoprotein in Cholesterol Transport

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