Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia

doi:10.1016/0021-9150(90)90086-X

Atherosclerosis

Volume 84, Issues 2–3, October 1990, Pages 155-163

https://doi.org/10.1016/0021-9150(90)90086-X Get rights and content

Abstract

Ordinarily, HDLI, a fraction of HDL enriched in apoE, is a minor fraction of plasma, but in human subjects and experimental animals eating diets high in fat and cholesterol and in patients with homozygous familial hypercholesterolemia (HFH) or CETP deficiency, HDL₁ (or HDL_c) concentrations in plasma are increased. However, little is known about the structures, compositions and metabolic sources of HDLI in HFH patients. To obtain HDL₁for the study, we surveyed several fractions in the HDL density range for apoE by SDS-PAGE. The ratio of apoE to apoAI in the HDL (d = 1.063–1.21 g/ml) of 8 HFH patients was 0.14 ± 0.03 compared to 0.03 ± 0.005 in a control group of 8 normolipidemic subjects (P < 0.001) suggesting that an apoE-rich fraction indeed was present in increased amounts. $ApoE apoAI$ ratios of lipoproteins of the density range 1.050–1.090 were even higher at 1.5 and 2.0 in 2 patients compared to 0.4 ± 0.1 in controls, indicating that this density fraction may be particularly enriched with apoE-rich lipoproteins. By contrast, d = 1.020–1.050 g/ml and d > 1.090 fractions contained very little apoE. Therefore, we further characterized the d = 1.050–1.090 g/ml lipoproteins of HFH patients and controls. Fractionation of an d = 1.050–1.090 fraction by concanavalin-A chromatography (CONA) yielded an unbound apoE-rich fraction that contained apoE, apoAI and apoC but no apoB, and a bound LDL-like fraction that contained mostly apoB-100, as determined by SDS-PAGE and by solid phase immunoassays, containing monoclonal antibodies directed against apoB, apoE and apoAI. The $apoE apoAI$ ratio of the CONA unbound fraction of HFH patients was greater, and the fraction also contained more free cholesterol and phospholipids than the fraction of control subjects. The diameters of these HDL₁ particles, determined by nondenaturing gradient gel electrophoresis, ranged from 12.2 to 17 run. HDL₁ of HFH patients were slightly larger than HDLI of controls. HDLI particles associated with and were degraded by cultured normal human skin fibroblasts with higher affinity than the LDL-like particles that were bound to the CONA column. Thus, in the composition and metabolic behavior HDL₁ isolated from the plasma of a fasted HFH patient resembled the HDL₁ (or HDL_c) seen in animals fed diets enriched in cholesterol and fats.

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HDL functionality in familial hypercholesterolemia: effects of treatment modalities and pharmacological interventions
2018, Drug Discovery Today
Citation Excerpt :
Several lines of evidence have shown that HDL2 particles can acquire apoE from arterial monocyte-derived macrophage foam cells and constitute apoE-containing HDL2 particles that can then be atherogenic [61]. The pool size of HDL-apoE in FH patients has been reported to be twofold higher than that in healthy subjects [62,63]. HDL-apoE has been proposed to bind to the extracellular proteoglycans, such as biglycan, and be retained in the arterial matrix of the atherosclerotic lesion [64–66].
Recent studies have demonstrated that assessment of high-density lipoprotein (HDL) functionality indices, instead of HDL cholesterol measurement, is a more robust tool for the evaluation of the functional status of HDL and cardiovascular risk. There are qualitative abnormalities of HDL particles in familial hypercholesterolemia (FH) patients that might represent potential therapeutic targets. Despite the potential promise of optimizing HDL functionality for the treatment of FH, there has been no prior comprehensive review focusing on the impact of different lipid-modifying therapies on HDL functionality in FH patients. In the present review, we aim to fulfill this gap and provide a concise summary on the impact of different lipid-modifying therapies on HDL functionality in FH.
LDL-apheresis depletes apoE-HDL and pre-β1-HDL in familial hypercholesterolemia: Relevance to atheroprotection
2011, Journal of Lipid Research
Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (−62%) and apoAI (−16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ∼1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ∼1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (−50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (−53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix.
A major gene influences variation in large HDL particles and their response to diet in baboons
2002, Atherosclerosis
Some baboons accumulate appreciable amounts of large apoE-rich HDLs (HDL₁) which are similar to those reported in humans with several different dyslipoproteinemias. We estimated HDL₁ cholesterol concentrations by gradient gel electrophoresis of serum samples obtained from 634 pedigreed baboons fed with three diets differing in levels of fat and cholesterol. The HDL₁ trait was highly heritable on each diet (0.390≤h²≤0.528). Segregation analyses yielded significant evidence that a single major gene plus polygenes affected HDL₁ on a high-fat low-cholesterol diet. The major gene explained approximately 56% of total trait variance and 90% of the additive genetic variance in HDL₁ levels in these baboons. Bivariate one-locus segregation analyses indicated that this major gene exerts significant pleiotropic effects on a number of traditional HDL traits on all three diets, including HDL size distributions, and concentrations of HDL-C, apoAI, and apoE. Linkage analyses showed that this major gene was not located in chromosomal regions that contain six candidate genes whose protein products are important to HDL metabolism (LCAT, CETP, APOA1, APOE, ABCA1, LIPC). Our results suggest this major gene in baboons plays a pivotal role in HDL metabolism, but is unlikely to code for any of the proteins previously implicated in studies of human HDL₁.
Catabolism of HDL1 cholesteryl ester in the rat. Effect of ethinyl estradiol treatment
1999, Comptes Rendus de l'Academie des Sciences - Serie III
The present study was performed in control and ethinyl estradiol-treated rats in order to determine the mechanisms involved in the catabolism of HDL1 cholesteryl ester. Ligand blottings on liver membranes showed that purified HDL1, containing about 70 % apolipoprotein E and 10 % apolipoprotein AI, bind to the LDL receptor (130 kDa) and not to HB2 (100 kDa) or SR-BI (82 kDa), candidate HDL receptors. Immunoblots showed that the treatment increased the hepatic level of the LDL receptor five- to ten-fold, strongly decreased that of SRBI and did not change that of HB2. An in vivo kinetic study showed that the turnover of HDL1 cholesteryl ester is more rapid in treated than control rats. The liver participation (60 %) in this clearance was not modified by the treatment. Therefore, it can be concluded that the catabolism of HDL1 cholesteryl ester, in control as in treated rats, is essentially ensured by the uptake of entire particles in the hepatocytes via LDL receptors.
Cette étude a été réalisée chez des rats témoins ou traités par de l'éthinyl estradiol pour mettre en évidence les mécanismes impliqués dans le catabolisme du cholestérol estérifié des HDL1. Il a été montré par ligand blotting sur membranes de foie que les HDL1 purifiées, contenant environ 70 % d'apolipoprotéine E et 10 % d'apolipoprotéine AI, se lient au récepteur LDL (130 KDa) et non à HB2 (100 KDa) ou SR-BI (82 KDa), candidats récepteurs aux HDL. Des immunoblots ont montré que le traitement augmentait de 5 à 10 fois le taux hépatique de récepteur LDL, diminuait très fortement celui de SR-BI et ne changeait pas celui de HB2. Une étude cinétique in vivo a montré que le renouvellement du cholestérol estérifié des HDL1 était plus rapide chez les rats traités que chez les témoins. La participation du foie (60 %) à cette clairance n'était pas modifiée par le traitement. Il peut être conclu que le catabolisme du cholestérol estérifié des HDL1, chez les rats témoins comme chez les traités, est assuré essentiellement par l'entrée dans l'hépatocyte de particules entières par les récepteurs LDL.
Comparison of the effect of fluvastatin, an hydroxymethyl glutaryl coenzyme A reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by apolipoprotein composition
1995, Metabolism
In a double-blind, parallel-group, randomized study, the effects of fluvastatin (FLUV) 20 and 40 mg/d on lipoprotein particle levels were compared with those of cholestyramine (CME) 16 g/d. Lipoparticles were defined by apolipoprotein composition as either those containing both apolipoprotein (apo) B and apo E or CHI (lipoprotein [Lp] E-B or Lp CIII-B) or those containing apo Al alone (Lp AI) or in association with apo AII (Lp AI-AII). After an 8-week dietary stabilization period, 100 hypercholesterolemic patients were treated with FLUV 20 mg/d for 6 weeks and 40 mg/d for an additional 6 weeks and were compared with 48 hypercholesterolemic subjects treated with CME 16 g/d. Treatment with FLUV (40 mg/d) or CME (16 g/d) for 12 weeks was associated with a significant reduction in plasma cholesterol and low-density lipoprotein (LDL) cholesterol and a significant increase in high-density lipoprotein (HDL) cholesterol. However, plasma triglyceride levels decreased following FLUV treatment, whereas they increased with CME. These changes were associated with a significant reduction in the levels of apo B (FLUV, −24%, P < .001; CME, −26%, P < .001), apo E (FLUV, −36%, P < .001; CME, −32%, P < .001), and apo CIII (FLUV, −21%, P < .001; CME, −6%, NS). The decreased levels of apo E and apo CIII were mainly due to a decrease in the apo B-containing fraction as assessed by the decrease in apo E (FLUV, −40%, P < .001; CME, −24.4%, P < .001) and apo CIII (FLUV, −50%, P < .05; CME, −33%, NS) that coprecipitated with apo B-containing lipoproteins and by the decrease in plasma levels of Lp E-B (FLUV, −25.8%, P < .001; CME, 2.3%, NS) and Lp CIII-B (FLUV, −48.8%, P < .001; CME, −34.1%, P < .001). With regard to apo AI-containing particles, significant effects were observed. Treatment with FLUV or CME increased plasma levels of apo AI (FLUV, +4.7%, P < .001; CME, +8.7%, P < .001) and Lp AI (FLUV, +10%, P < .001; CME, +25.5%, P < .001) and decreased Lp AI-AII (FLUV, −5.7%, NS; CME, −11.5%, P < .05). FLUV or CME decreased apo E bound to HDL (−36.8%, P < .001, and −50%, P < .001, respectively). In summary, treatment with FLUV or CME was associated with beneficial changes in plasma lipid, lipoprotein, apolipoprotein, and lipoparticle levels. FLUV is more efficient in reducing levels of atherogenic apo B-containing particles, whereas CME has a greater effect in increasing the levels of Lp AI.
Separation oa ApoA- and ApoB-containing lipoproteins of human plasma by affinity chromatography on concanavalin A
1991, Progress in Lipid Research

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Research paperApolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia

Abstract

Atherosclerosis

J. Lipid Res.

Atherosclerosis

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Lipid Res.

Anal. Biochem.

J. Biol. Chem.

J. Lipid Res.

J. Lipid Res.

J. Biol. Chem.

Metabolism

J. Lipid Res.

Research paper
Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia