Structural and functional properties of human plasma high density-sized lipoprotein containing only apoE particles

Krimbou, Larbi; Marcil, Michel; Chiba, Hitoshi; Genest, Jacques

doi:10.1194/jlr.m200273-jlr200

Cited by 49 publications

(61 citation statements)

References 48 publications

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“…ApoE-containing plasma HDL, which belong to HDL 2 subclass (d=9-17 nm) (34,35), are similar in size to apoE-containing HDL-like particles observed in this work ( Fig. 4C, E; Fig.…”

Section: Discussionsupporting

confidence: 59%

“…In plasma, apoE facilitates CE core expansion in HDL and thereby plays an important role in HDL metabolism, particularly in case of cholesterol ester transfer protein deficiency (33,34). Thus, apoE-containing HDL, which may be generated during lipolysis of TG-rich proteins, are important players in lipoprotein metabolism.ApoE-containing plasma HDL, which belong to HDL 2 subclass (d=9-17 nm) (34,35), are similar in size to apoE-containing HDL-like particles observed in this work ( Fig. 4C, E; Fig.…”

supporting

confidence: 59%

“…therein). In plasma, apoE facilitates CE core expansion in HDL and thereby plays an important role in HDL metabolism, particularly in case of cholesterol ester transfer protein deficiency (33,34). Thus, apoE-containing HDL, which may be generated during lipolysis of TG-rich proteins, are important players in lipoprotein metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Thermal Transitions in Human Very-Low-Density Lipoprotein: Fusion, Rupture, and Dissociation of HDL-like Particles

et al. 2007

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Very low-density lipoproteins (VLDL) are metabolic precursors of low-density lipoproteins (LDL) and a risk factor for atherosclerosis. Human VLDL are heterogeneous complexes containing triacylglyceride-rich apolar lipid core and polar surface comprised of phospholipids, a nonexchangeable apolipoprotein B, and exchangeable apolipoproteins E and Cs. We report the first stability study of VLDL. Circular dichroism and turbidity data reveal an irreversible heat-induced VLDL transition that involves formation of larger particles and repacking of apolar lipids but no global protein unfolding. Heating rate effect on the melting temperature indicates a kinetically controlled reaction with high activation energy, E a . Arrhenius analysis of the turbidity data reveals two kinetic phases with E a =53±7 kcal/mol that correspond to distinct morphological transitions observed by electron microscopy. One transition involves VLDL fusion, partial rupture and dissociation of small spherical particles (d=7-15 nm), and another involves complete lipoprotein disintegration and lipid coalescence into droplets accompanied by dissociation of apolipoprotein B. The small particles, which are unique to VLDL denaturation, are comparable in size and density to high-density lipoproteins (HDL); they have apolar lipid core and polar surface comprised of exchangeable apolipoproteins (E and possibly Cs) and phospholipids. We conclude that, similar to HDL and LDL, VLDL are stabilized by kinetic barriers that prevent particle fusion and rupture and decelerate spontaneous inter-conversion among lipoprotein classes and subclasses. In addition to fusion, VLDL disruption involves transient formation of HDL-like particles that may mimic protein exchange among VLDL and HDL pools in plasma.Plasma lipoproteins, including high-, low-, intermediate-, and very-low density lipoproteins (HDL, LDL, IDL and VLDL), are macromolecular complexes of lipids and proteins (termed apolipoproteins) that mediate lipid transport and metabolism and are central in the development of coronary artery disease. HDL are anti-atherogenic, LDL are pro-atherogenic, and VLDL are not only direct metabolic precursors of LDL but also an independent risk factor for atherosclerosis (1)(2)(3)(4)(5)(6)(7)(8). VLDL are the major carriers of triacylglycerides (TG) in plasma. Human VLDL form heterogeneous population of spherical particles that contain apolar core comprised mainly of TG and cholesterol esters (CE) and polar surface comprised of cholesterol-containing phospholipid monolayer and proteins. The proteins include one copy of non-exchangeable apolipoprotein B (apoB, 550 kD) and multiple copies of exchangeable apolipoproteins, mainly apoE (34 kD) and apoCs (6-9 kD), that comprise over 50% of the total VLDL protein content. Metabolic remodeling by lipolytic enzymes converts VLDL into LDL that contain apoB as their sole protein, while the dissociated apoE and apoCs enter the HDL pool (2,4). Structural Our recent thermal and chemical denaturation analyses have shown that HDL and LDL...

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“…ApoE-containing plasma HDL, which belong to HDL 2 subclass (d=9-17 nm) (34,35), are similar in size to apoE-containing HDL-like particles observed in this work ( Fig. 4C, E; Fig.…”

Section: Discussionsupporting

confidence: 59%

supporting

confidence: 59%

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Thermal Transitions in Human Very-Low-Density Lipoprotein: Fusion, Rupture, and Dissociation of HDL-like Particles

et al. 2007

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“…As summarized in the introductory paragraphs, the physiological functions of the apoE molecule involve various binding events that are mediated by amphipathic α-helices located in the N-and C-terminal domains. After dissociation of apoE tetramers [such as occur in plasma HDL-LpE (35)] to the monomeric state (15,47), the C-terminal helical domain initiates hydrophobic interactions such as binding to lipid and lipoprotein surfaces (7,44), and to amyloid-β (13,48). The present HX results prove that the amphipathic α-helix organization in the C-terminal domains of tetrameric WT apoE3 and apoE4 is different and suggest the following explanation for the molecular basis of the enhanced binding of apoE4 in such situations.…”

Section: Influence Of Differences In Secondary Structure On Apoe3 Andmentioning

confidence: 99%

“…This pool of plasma apoE has been identified and designated HDL-LpE (35). In normolipidemic individuals, its concentration is ∼0.2 μM and it accounts for ∼20% of total plasma apoE.…”

mentioning

confidence: 99%

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

Chetty

Mayne

Lund‐Katz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen−deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four α-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an α-helix ∼70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3.apolipoprotein E | hydrogen exchange mass spectrometry | cholesterol | protein secondary structure | amphipathic helix

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Apolipoprotein E and Reverse Cholesterol Transport: The Role of Recycling in Plasma and Intracellular Lipid Trafficking

Swift

Hasty

Linton

et al. 2007

High‐Density Lipoproteins

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Apolipoprotein E (apoE) is unique among the apoproteins because of its many different functions in biology, ranging from modulation of plasma lipoprotein metabolism, through control of cellular cholesterol homeostasis, to regulation of neuronal function. Although apoE is synthesized by several tissues and cell types, its circulating levels are influenced primarily by the liver. Within the plasma compartment apoE readily redistributes among chylomicrons, remnant particles, and high-density lipoproteins (HDL), where it has functional roles both in directing triglyceride-rich particles to sites of catabolism and clearance and in determining size expansion of the HDL. Its role as a ligand for the receptor-mediated endocytosis of lipoproteins is well established [1-3]. It is recognized by the low-density lipoprotein (LDL) receptor (LDLR) [2,3], the LDLR-related protein 1 (LRP1) [1,4,5], and heparan sulfate proteoglycans (HSPG), either alone [6,7] or in concert with the LRP1 [8]. Additionally, within the periphery apoE interacts with lipoprotein lipase (LPL) and hepatic lipase (HL) to modulate triglyceride hydrolysis [9,10]. Within the cell apoE is known to serve many biologically relevant roles. Studies have suggested that apoE directs the intracellular routing of internalized remnant lipoproteins [11,12] and modulates intracellular lipid metabolism, in particular the hydrolysis and utilization of triglyceride [13]. In hepatocytes, it plays a critical role in the assembly and secretion of VLDL, augmenting the incorporation of triglycerides into newly forming particles [14][15][16]. Finally, apoE is a critical component of the reverse cholesterol transport (RCT) pathway. It promotes cholesterol efflux from macrophages [17-19] and plays major roles in HDL formation, maturation, and hepatic uptake, as well as in the selective uptake of HDL cholesteryl ester by the liver [20][21][22][23]. ApoE is also expressed by macrophage-derived foam cells, while a number of studies support an important antiatherogenic role for macrophage apoE in vivo [24][25][26][27].The unique nature of apoE is also demonstrated by the fact that, after internalization, this apoprotein follows specialized cellular pathways allowing it to exert maximum impact on cellular lipid homeostasis. In particular, studies both in our High-Density Lipoproteins: From Basic Biology to Clinical Aspects. Edited by Christopher J. Fielding

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Structural and functional properties of human plasma high density-sized lipoprotein containing only apoE particles

Cited by 49 publications

References 48 publications

Thermal Transitions in Human Very-Low-Density Lipoprotein: Fusion, Rupture, and Dissociation of HDL-like Particles

Thermal Transitions in Human Very-Low-Density Lipoprotein: Fusion, Rupture, and Dissociation of HDL-like Particles

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

Apolipoprotein E and Reverse Cholesterol Transport: The Role of Recycling in Plasma and Intracellular Lipid Trafficking

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