Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: structure of low and high density lipoproteins as revealed by electron microscopy

Forte, Trudy; Norum, Kaare R.; Glomset, John A.; Nichols, Alex V.

doi:10.1172/jci106586

Cited by 238 publications

(88 citation statements)

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“…A) The left column shows top views of the nanodiscs, whereas the right column shows side views of nanodiscs that are stacked on top of each other. Stacking arises from EM grid preparation and is a common feature of discoidal nanodiscs 5, 18…”

Section: Resultsmentioning

confidence: 99%

Lipid Internal Dynamics Probed in Nanodiscs

et al. 2017

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Nanodiscs offer a very promising tool to incorporate membrane proteins into native‐like lipid bilayers and an alternative to liposomes to maintain protein functions and protein–lipid interactions in a soluble nanoscale object. The activity of the incorporated membrane protein appears to be correlated to its dynamics in the lipid bilayer and by protein–lipid interactions. These two parameters depend on the lipid internal dynamics surrounded by the lipid‐encircling discoidal scaffold protein that might differ from more unrestricted lipid bilayers observed in vesicles or cellular extracts. A solid‐state NMR spectroscopy investigation of lipid internal dynamics and thermotropism in nanodiscs is reported. The gel‐to‐fluid phase transition is almost abolished for nanodiscs, which maintain lipid fluid properties for a large temperature range. The addition of cholesterol allows fine‐tuning of the internal bilayer dynamics by increasing chain ordering. Increased site‐specific order parameters along the acyl chain reflect a higher internal ordering in nanodiscs compared with liposomes at room temperature; this is induced by the scaffold protein, which restricts lipid diffusion in the nanodisc area.

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Section: Resultsmentioning

confidence: 99%

Lipid Internal Dynamics Probed in Nanodiscs

et al. 2017

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“…The initial observation of discoidal HDL particles was made by Forte et al (2) when they examined HDL from patients with familial lecithin:cholesterol acyltransferase deficiency by negative stain EM. Reconstituted apoA-I/HDL particles (3) and nascent HDL from lymph (4) were then observed by negative stain EM to also have a discoidal shape.…”

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confidence: 99%

Assessment of the Validity of the Double Superhelix Model for Reconstituted High Density Lipoproteins

Jones

Zhang

Catte

et al. 2010

Journal of Biological Chemistry

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High density lipoproteins (HDL) represent a heterogeneous population of particles with apoA-I as the major protein (1). Whether apoA-I/HDL 2 plays a direct role in cardiovascular disease prevention (e.g. removal of cholesterol from clogged arteries) or an indirect one (e.g. acts as a platform for the clustering of protective molecules, such as anti-inflammatory or antioxidant proteins), detailed knowledge of HDL structure is a key to understanding the molecular mechanism underlying these processes. Because the conformation of apoA-I on HDL is highly plastic (1), understanding apoA-I/HDL structure and dynamics is not straightforward.Since the early 1970s, the standard model for HDL particles reconstituted from apolipoprotein A-I (apoA-I) and phospholipid (apoA-I/HDL) has been that of a discoidal particle on the order of 100 Å in diameter and the thickness of a phospholipid bilayer. The initial observation of discoidal HDL particles was made by Forte et al. (2) when they examined HDL from patients with familial lecithin:cholesterol acyltransferase deficiency by negative stain EM. Reconstituted apoA-I/HDL particles (3) and nascent HDL from lymph (4) were then observed by negative stain EM to also have a discoidal shape. X-ray and neutron scattering studies (5, 6) provided further support for the standard discoidal model. The standard discoidal model has been used to interpret the results of a large number of experimental studies of the structure of reconstituted apoA-I/HDL particles. For review, see however, Wu et al. (11) used small angle neutron scattering to develop a model for apoA-I/HDL particles that is dramatically different from the standard model. In their model, termed a double superhelix (DSH), apoA-I possesses an open helical shape that twists around a central prolate ellipsoidal particle resembling a partial type I hexagonal lyotropic liquid crystalline phase.The DSH model is interesting. It is similar to MD simulation-based models (12) in that the proposed double superhelix forms a left-handed spiral as it wraps around the prolate ellip-

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“…In LCAT-def, HDL is markedly decreased, together with abnormalities in size and lipid composition. 2 Most of the HDL in LCAT-def is small and discoidal, 3 a characteristic resembling newly synthesized HDL. 4,5 In the absence of LCAT, newly synthesized HDL cannot esterify FC to CE in its core so that HDL cannot develop into its mature stable forms of either HDL 3 or HDL 2 .…”

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confidence: 99%

Human Lecithin:Cholesterol Acyltransferase Deficiency

Nishiwaki

Ikewaki

Bader

et al. 2006

ATVB

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Objectives-Lecithin:cholesterol acyltransferase deficiency (LCAT-def) is characterized by low levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) and the accumulation of lipoprotein-X (LpX). Despite the low HDL, atherosclerosis is uncommon in LCAT-def. The decreased LDL would be a possible explanation but the underlying mechanism is not clear. In addition, the mechanism(s) for LpX accumulation is not known. The aim of the present study is to elucidate the mechanism(s) responsible for the low LDL and determine the plasma kinetics of LpX in LCAT-def. Methods and Results-We conducted a radiotracer study in LCAT-def (nϭ2) and normal controls (nϭ10) and a stable isotope study in one patient and other controls (nϭ7). LCAT-def LDL was catabolized faster than control LDL in the control subjects as well as in LCAT-def patients. Control LDL was catabolized faster in LCAT-def patients than the controls. The production rate of LDL apolipoprotein B-100 was normal in LCAT-def. The increased LDL apoB-100 catabolism was confirmed by a stable isotope study. LpX was catabolized more slowly in LCAT-def. (HDL). Human LCAT deficiency (LCAT-def) is characterized by corneal opacity, anemia, and proteinuria, 1 with low levels of HDL and LDL and the accumulation of lipoprotein-X (LpX). In LCAT-def, HDL is markedly decreased, together with abnormalities in size and lipid composition. 2 Most of the HDL in LCAT-def is small and discoidal, 3 a characteristic resembling newly synthesized HDL. 4,5 In the absence of LCAT, newly synthesized HDL cannot esterify FC to CE in its core so that HDL cannot develop into its mature stable forms of either HDL 3 or HDL 2 . 6 This process of HDL maturation is important for reverse cholesterol transport, a hypothesis that HDL transports CE from peripheral atherosclerotic lesions to the liver. This hypothesis is based on epidemiological studies that indicated an inverse correlation between the HDL cholesterol (HDL-C) levels and the prevalence of coronary heart disease (CHD) as an independent anti-atherogenic factor for CHD. 7 It is therefore interesting to note that despite a markedly low level of HDL-C and a loss of the HDL maturation process, CHD is Conclusions-The decreased LDL in LCAT- See page 1201not a common complication in LCAT-def patients. 8,9 Gylling 10 reported the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased in LCAT-def. The accompanying low level of LDL is perhaps the reasonable explanation for the low incidence of CHD in LCAT-def. Studies dealing with abnormalities in LDL lipid composition in LCAT-def reported that LCAT-def LDL (L-LDL) has higher amounts of triglyceride (TG), phospholipids (PL), and FC, and an extremely low amount of CE. 11 In plasma, lipoprotein lipase (LPL) and hepatic lipase (HL) catalyze the lipolysis of TG in TG-rich lipoproteins such as chyromicron and very-low-density lipoprotein (VLDL). L-LDL rich in TG may be also affected by LPL and HL, although the influence of these enzymes on normal LDL (N-...

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Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: structure of low and high density lipoproteins as revealed by electron microscopy

Abstract: A B S T R A C T The low density lipoproteins (LDL)

Cited by 238 publications

References 10 publications

Lipid Internal Dynamics Probed in Nanodiscs

Lipid Internal Dynamics Probed in Nanodiscs

Assessment of the Validity of the Double Superhelix Model for Reconstituted High Density Lipoproteins

Human Lecithin:Cholesterol Acyltransferase Deficiency

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