Volumetric determination of apolipoprotein stoichiometry of circulating HDL subspecies

Segrest, Jere P.; Cheung, Marian C.; Jones, Martin K.

doi:10.1194/jlr.m039172

Cited by 23 publications

(41 citation statements)

References 45 publications

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“…HDL size by NMR has been shown to agree with those by gradient gel electrophoresis (GGE) ( 10,44 ) and compositional analysis ( 41 ). Published values for LDL radius by NMR have been identical to those by cryo-electron microscopy ( 45 ) and composition analysis ( 46 ), but to be smaller than that by GGE ( 10,47 ).…”

Section: Discussionsupporting

confidence: 52%

“…As apo AI is present in all HDLs and is unique to this lipoprotein class in fasted healthy humans, its concentration in plasma refl ects HDL particle number ( 10,40 ). As the number of apo AI molecules per particle varies, most containing three or four ( 41 ), and the relative proportions of different particles varies between subjects, the correlation between plasma apo AI concentration and HDL particle number in populations is nonlinear ( 42 ). However, this does not undermine our use of apo AI as a marker of the relative concentrations of HDL in plasma and lymph within subjects for calculating clearance rate, unless there is a preferential transfer of a specifi c HDL subclass across the endothelium.…”

Section: Resultsmentioning

confidence: 99%

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LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

Michel

Nanjee

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org chylomicrons and VLDLs, are limited in distribution to blood and metabolized at the luminal surface of vascular endothelium by lipoprotein lipase. By contrast, the LDLs and HDLs move between plasma and interstitial fl uid as they transport lipids to and from different cell types. Each LDL particle contains a single molecule of apoB100 (apo B) ( 1, 2 ). The principal protein component of all HDL particles is apo AI, which usually accounts for about 70% of total HDL protein mass. Some HDLs also contain apo AII as the second most abundant protein ( 3 ). Studies of human afferent peripheral lymph have shown that the concentrations of apo AI and apo AII in normal human interstitial fl uid average about one-fi fth of those in plasma ( 4-6 ), while lymph apo B concentration averages only one-tenth ( 4, 7 ). The ratio of HDL to LDL particles in interstitial fl uid has been estimated to average about 50:1 in healthy humans ( 4,8 ).The striking differences in lipoprotein concentrations between plasma and interstitial fl uid, combined with their roles in atherosclerosis, highlight the importance of understanding the mechanisms by which they move into and out of the extravascular compartment. By analyzing data on adipokines of different molecular size, Miller et al. ( 9 ) showed that the principal pathway by which a macromolecule leaves the interstitium of peripheral tissues in humans is determined by its size, the proportion leaving via capillaries decreasing and that via the lymphatic system increasing, as molecular radius rises. As proteins of radius у 3.2 nm were found to leave entirely in lymph, it is reasonable to assume that this applies also to LDL and HDL, given that their radii greatly exceed this fi gure ( 10,11 ). This interpretation agrees with recent studies of HDL transport via the lymphatic system in mice ( 12 ).The mechanisms by which HDL and LDL are transported from plasma into interstitial fl uid are not understood. Two

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

Michel

Nanjee

et al. 2015

Journal of Lipid Research

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“…15 That means the reduced thickness of protein which allows increased exposure of amino acid residues to external medium. The shift of the stretching band of ester group is the result of increased contribution of vibrations from triglycerides in LDL-B core and diminished contribution of surface lipids.…”

Section: Discussionmentioning

confidence: 99%

Structural and Oxidation Properties of Plasma Lipoproteins from Different Phenotypes: FT-IR and ESR Study

Krilov¹,

Kosović²,

Brnjas-Kraljević³

et al. 2013

Croat. Chem. Acta

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Abstract. Subclasses of lipoproteins VLDL, LDL and HDL were isolated from plasma of two different phenotypes, A and B. Phenotype B is present in people with diabetes, atherosclerosis and higher risk for cardiovascular disease. Lipoproteins were studied by FT-IR spectroscopy to investigate conformational and structural differences reflected in spectra. Differences were observed in spectra of LDL and VLDL. In protein domain differences were observed in amide I band profile and discussed in terms of conformational change of apo B-100 in small LDL and large VLDL particles. The changes in lipid bands from phenotype B are associated with differences in core composition and lipids' ordering in monolayer. The study of slow oxidation was done by measuring the oxygen consumption in lipoprotein solutions. Oxidation was faster in HDL and VLDL from phenotype B, while for LDL it was similar for A and B samples and significantly faster than in other two lipoproteins. (doi: 10.5562/cca2236)

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“…As described Ref. 41 , we developed a volumetric analysis procedure for selecting native sHDL protein and lipid stoichiometries ( 21 ) for best fi ts to dimensions determined by nondenaturing gradient gel electrophoresis (NDGGE) for HDL isolated by immunoaffi nity chromatography ( 42 ) [7] are described in Table 3 [4], and HDL [7] being predominantly LpA-I (particles with apoA-I but without apoA-II).…”

Section: Simulations Of Native Circulating Shdl Particles Containing mentioning

confidence: 99%

MD simulations suggest important surface differences between reconstituted and circulating spherical HDL

Segrest

Jones

Catte

2013

Journal of Lipid Research

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The common lipid-associating motif in apoA-I is the amphipathic ␣ helix ( 2, 3 ). The fi rst tangible experimental evidence for the conformation of apoA-I on the edge of discoidal HDL (dHDL) was determination of a 4 Å resolution solution phase X-ray structure for residues 44-243 of lipid-free apoA-I reported by Borhani et al. in 1997 ( 4 ) that suggested an antiparallel double-belt model. In the fi rst experimental test of the belt model, Axelsen et al. ( 5 ) used polarized attenuated total internal refl ection Fourier-transform infrared spectroscopy to conclude that the result unambiguously supported a belt model. Theoretical considerations of the geometric and physical chemical nature of the apoA-I double-belt model resulted in the publication by our lab of an atomic resolution, antiparallel, double-belt, amphipathic helical model for dHDL ( 6 ) with a helix-helix registry termed LL5/5 oriented by salt bridges ( 6 ) surrounding the edge of a bilayer disc. Five laboratories subsequently have studied reconstituted dHDL using a variety of physical chemical methods, and the results have been consistent with our double-belt model ( 7-11 ). This model provided sound theoretical rationale for use of the lipid-free X-ray crystal structure as a valid model for molecular dynamics (MD) simulations of lipid-associated apoA-I. Comparison of the results of our MD simulations of the antiparallel, full-length apoA-I structure from an ensemble of 16 MD simulations of 105 Å dHDL ( 12-15 ) with the highresolution C-truncated crystal structure of apoA-I by Mei and Atkinson ( 16 ) validates many of our key published MD fi ndings ( 17 ).We previously published MD simulations of sHDL using N-terminally truncated ( ⌬ 43)apoA-I ( 18 ). We also investigated the dynamics of the activation of LCAT by apoA-I using both all-atom (AA) and coarse-grained (CG) MD Abstract Since spheroidal HDL particles (sHDL) are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models. Here we use MD to simulate sHDL with stoichiometries of reconstituted and circulating particles. The hydrophobic effect during simulations rapidly remodels discoidal HDL containing mixed lipids to sHDL containing a cholesteryl ester/triglyceride (CE/TG) core. We compare the results of simulations of previously characterized reconstituted sHDL particles containing two or three apoA-I created in the absence of phospholipid transfer protein (PLTP) with simulations of circu lating human HDL containing two or three apoA-I without apoA-II. We fi nd that circulating sHDL compared with reconstituted sHDL with the same number of apoA-I per particle contain approximately equal volumes of core lipid but signifi cantly less surface lipid monolayers. We conclude that in vitro reconstituted sHDL particles contain kinetically trapped excess phospholipid and are less than ideal models for circulating sHDL particles. In the circulation, phospholipid transfer via PLTP decreases the ratio of phospholipid to apolipoprotein for all sHDL particles. Further, sH...

show abstract

Volumetric determination of apolipoprotein stoichiometry of circulating HDL subspecies

Cited by 23 publications

References 45 publications

LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

Structural and Oxidation Properties of Plasma Lipoproteins from Different Phenotypes: FT-IR and ESR Study

MD simulations suggest important surface differences between reconstituted and circulating spherical HDL

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