Influence of ApoE Content on Receptor Binding of Large, Buoyant LDL in Subjects With Different LDL Subclass Phenotypes

Abstract

Abstract-We investigated the influence of apolipoprotein (apo) E-containing particles on LDL receptor binding of large, buoyant LDL subfractions (LDL I) from subjects with predominantly large (phenotype A) and small (phenotype B) LDL particles. Direct binding by human fibroblast LDL receptors was tested at 4°C before and after removal of apoE-containing particles by immunoaffinity chromatography. The binding affinity of total LDL I in phenotype B was greater than that in phenotype A (Kd of 1.83Ϯ0.3 and 3.43Ϯ0.9 nmol/L, respectively, PϽ.05). LDL I from phenotype B subjects had a higher apoE to apoB molar ratio than did that from phenotype A (0.16Ϯ0.04 versus 0.06Ϯ0.02, PϽ.05). Nondenaturing gradient gel electrophoresis of apoE-containing LDL I isolated by immunoaffinity chromatography revealed a substantially larger peak particle diameter than in apoE-free LDL I, and comparison of LDL I composition before and after immunoaffinity chromatography suggested an increase in triglyceride content of apoE-containing particles. After removal of these particles, there was a greater than twofold reduction in LDL receptor affinity of phenotype B LDL (Kd of 1.83Ϯ0.3 to 3.76Ϯ0.6, PϽ.01), whereas in phenotype A no change was observed (Kd of 3.43Ϯ0.9 to 3.57Ϯ0.4, respectively). The receptor affinity of apoE-free LDL I from phenotype A and B subjects did not differ. These findings confirm that large, buoyant LDL particles from phenotype B subjects have a higher LDL receptor affinity than does LDL I from phenotype A subjects and suggest that this difference is due to an increased content of large, triglyceride-enriched, apoE-containing lipoproteins. 1,2 On the basis of differences in LDL subclass profiles as determined by GGE, individuals may be categorized as having a predominance of large (phenotype A) or small (phenotype B) LDL particles.3 Phenotype B is associated with increased plasma triglyceride levels, reduced HDL cholesterol levels, and as much as a threefold increase in risk for coronary artery disease. 4,5 Phenotype B, at least in part, is genetically determined but is also strongly influenced by sex, age, and environmental factors, including abdominal obesity, oral contraceptive use, and dietary fat and carbohydrate intake. -10We recently evaluated whether differences in the binding of LDL to fibroblast LDL receptors might contribute to the different LDL subclass distributions in phenotype A and B subjects.11 In phenotype A subjects, we found that, consistent with other reports, 12-17 LDL receptor binding affinity was higher in fractions containing LDL of mid-range size and density than in fractions containing either large, buoyant LDL or small, dense LDL. In phenotype B, the binding affinities of both mid-range and small LDL were similar to those for phenotype A, but the affinity for large LDL (ie, LDL I) was significantly greater.11 The apoE content of large, buoyant LDL fractions was also higher in LDL I from phenotype B subjects. 11Particles with additional apoE have been shown to have greater LDL receptor binding ...

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

“…ApoE is mainly expressed in astrocytes and microglia and appears as three major isoforms, ApoE2, ApoE3, and ApoE4, of which ApoE4 is the strongest genetic risk factor for AD (Stone et al, 1997;Ito et al, 2005;Vance and Hayashi, 2010;Chung et al, 2016;Liu et al, 2017;Montoliu-Gaya et al, 2018;Tulloch et al, 2018). ApoE4 demonstrates a lower affinity for lipids than ApoE2 and ApoE3, limiting CNS transport of lipids needed for neuronal remodeling and repair (Bradley and Gianturco, 1986;Barbagallo et al, 1998;Li et al, 2002;Frieden et al, 2017). Furthermore, levels of ApoE LDL receptors directly correlate with Aβ clearance, and promoting…”

Computational Lipidology: Predicting Lipoprotein Density Profiles in Human Blood Plasma

“…However, such model-based optimization of systemic lipid diagnostics requires extensive improvements of the core model presented in this paper. The most relevant extensions and refinements necessary to increase the physiological reliability of the model are as follows: (i) inclusion of apoA-II (P02652, ENSG00000158874) to allow for differentiation between LpA-I and LpA-I:A-II particles to better satisfy the differing metabolic behavior of several HDL sub-populations in normal and pathological conditions [25],[40]; (ii) inclusion of apoB-48 in addition to apoB-100 to model the metabolism of intestinal synthesized chylomicrons even with respect to postprandial hyperlipidemia [41],[42]; (iii) distinguishing between free cholesterol and cholesteryl ester and inclusion of the esterification process of free cholesterol by LCAT [43]; (iv) disaggregation of the model component variable F into apolipoproteins E and C and explicit consideration of the regulatory function of these isoforms (e.g., activating effect of apoC-I [P02654, ENSG00000130208] on LCAT [44], activation of LPL by apoC-II [P02655, ENSG00000213044] [26], influence on the LDL receptor binding by apoE [45], and the apoE-dependent alternative path for peripheral cholesterol [46]); (v) explicit incorporation of the phospholipid exchange mediated by the phospholipid transfer protein (PLTP; P55058, ENSG00000100979) playing a key role in the remodeling of HDL [47],[48]; and (vi) inclusion of other transporters and receptors involved either in the holoparticle uptake or in the uptake of individual lipoprotein components, e.g., SR-B1 (Q8WTV0, ENSG00000073060), ABCG1 (P45844, ENSG00000160179), and ABCG4 (Q9H172, ENSG00000172350) [49],[50].…”

Independent Effects of Apo E Phenotype and Plasma Triglyceride on Lipoprotein Particle Sizes in the Fasting and Postprandial States

“…40 Recent studies have also demonstrated an effect of apo E containing particles on LDL receptor binding of buoyant LDL, which differs between subjects with predominantly small or large LDL particles. 41 In the present study, we have examined the relationships between LDL and HDL particle sizes, determined aftergradient gel electrophoresis, and apo E phenotypes, in particular the possession of ⑀4 and ⑀2 alleles in control subjects and those with CHD. The role of plasma triglyceride in effecting such modulations has been determined, with particular attention to postprandial changes in HDL particles.…”