scholarly journals Regulation of plasma LDL: the apoB paradigm

2009 ◽  
Vol 118 (5) ◽  
pp. 333-339 ◽  
Author(s):  
Allan D. Sniderman ◽  
Jacqueline De Graaf ◽  
Patrick Couture ◽  
Ken Williams ◽  
Robert S. Kiss ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Critical Aspect ◽  
Lipoprotein Particles ◽  
Ldl Particles ◽  
Plasma Compartment

The objectives of this analysis are to re-examine the foundational studies of the in vivo metabolism of plasma LDL (low-density lipoprotein) particles in humans and, based on them, to reconstruct our understanding of the governance of the concentration of plasma LDL and the maintenance of cholesterol homoeostasis in the hepatocyte. We believe that regulation of cholesterol homoeostasis within the hepatocyte is demonstrably more complex than envisioned by the LDL receptor paradigm, the conventional model to explain the regulation of plasma LDL and the fluxes of cholesterol into the liver, a model which was generated in the fibroblast but has never been fully validated in the hepatocyte. We suggest that the LDL receptor paradigm should be reconfigured as the apoB (apolipoprotein B) paradigm, which states that the rate at which LDL particles are produced is at least an important determinant of their concentration in plasma as the rate at which they are cleared from plasma and that secretion of cholesterol within VLDL (very-low-density lipoprotein) particles is an important mechanism of maintaining cholesterol homoeostasis within the hepatocyte. These two paradigms are not mutually exclusive. The LDL receptor paradigm, however, includes only one critical aspect of the regulation of plasma LDL, namely the rate at which LDL particles are cleared through the LDL receptor pathway, but ignores another – the rate at which LDL particles are added to the plasma compartment. The apoB paradigm includes both and points to a different model of how the hepatocyte achieves cholesterol homoeostasis in a complex metabolic environment.

scholarly journals Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

1986 ◽  
Vol 234 (1) ◽  
pp. 245-248 ◽  
Author(s):  
W Jessup ◽  
G Jurgens ◽  
J Lang ◽  
H Esterbauer ◽  
R T Dean
Keyword(s):  
Apolipoprotein B ◽  
Negative Charge ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipid Peroxidation Product ◽  
Modified Low Density Lipoproteins ◽  
Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

scholarly journals Rabbit and rat C-reactive proteins bind apolipoprotein B-containing lipoproteins.

1984 ◽  
Vol 159 (2) ◽  
pp. 604-616 ◽  
Author(s):  
I F Rowe ◽  
A K Soutar ◽  
I M Trayner ◽  
M L Baltz ◽  
F C de Beer ◽  
...  
Keyword(s):  
Acute Phase ◽  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasma Lipoproteins ◽  
Free Form ◽  
Low Density ◽  
Serum Samples ◽  
Acute Phase Serum

Immobilized rabbit and rat C-reactive protein (CRP) were found to selectively bind apolipoprotein B (apoB)-containing lipoproteins (low density lipoprotein, LDL and very low density lipoprotein, VLDL) from whole serum in a manner similar to that previously reported with human CRP. In acute phase human serum the CRP is in a free form, not complexed with lipoprotein or any other macromolecular ligand, and in acute phase serum from most rabbits fed on a normal diet the rabbit CRP was also free. However, in acute phase serum or heparinized plasma from hypercholesterolemic rabbits part or all of the CRP was found by gel filtration and immunoelectrophoretic techniques to be complexed with beta-VLDL, an abnormal apoB-containing plasma lipoprotein present in these animals. The presence of extent in different serum samples of CRP complexed with lipoprotein correlated closely with the serum apoB concentration. The formation of complexes between native, unaggregated rabbit CRP in solution and apoB-containing lipoproteins was readily demonstrable experimentally both with the isolated proteins and in whole serum. In all cases these interactions were calcium-dependent and inhibitable by free phosphoryl choline. The present findings extend earlier work in man and the rabbit and indicate that among the C-reactive proteins from different species, which are structurally highly conserved, the capacity for selective binding to apoB-containing plasma lipoproteins is also a constant feature. These interactions may therefore be related to the in vivo function of CRP in all species and this function may in turn be relevant to pathological conditions, such as atherosclerosis, in which lipoproteins are important.

scholarly journals Measurement of the absolute number of functioning low-density lipoprotein receptors in vivo using a monoclonal antibody

1995 ◽  
Vol 305 (3) ◽  
pp. 897-904 ◽  
Author(s):  
C Fitzsimmons ◽  
R Bush ◽  
D Hele ◽  
C Godliman ◽  
E Gherardi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Absolute Number ◽  
Low Density ◽  
Ldl Receptors ◽  
The Absolute

MAC188 S/S is a monoclonal antibody which can be used in vivo to measure the absolute number of functioning low-density lipoprotein (LDL) receptors in a rabbit. The antibody binds to the extra-cellular domain of the LDL receptor and binding is not blocked by the presence of LDL. When the antibody-receptor complex is internalized, receptor recycling is inhibited for several hours. Thus when saturating doses of MAC188 S/S are administered intravenously, the amount of antibody removed from the blood (minus non-specific removal) is determined solely by the total number of LDL receptors in an animal. In this study MAC188 S/S was used to measure the number of LDL receptors in control rabbits and in animals treated with 17 alpha-ethinyl oestradiol. After treatment (which caused a 47% decrease in plasma cholesterol), receptor-mediated removal of MAC188 S/S from the blood was saturated in both groups following injection of 3.0 mg of antibody per kg body weight. Based on the amount of antibody removed via the LDL receptor at this dose, the total number of accessible LDL receptors was calculated as (2.0 +/- 0.3) x 10(15) receptors per kg body weight in control rabbits and (4.0 +/- 0.4) x 10(15) receptors per kg body weight in oestrogen-treated animals. The number of receptors in various organs was also determined. The monoclonal antibody approach therefore, allows accurate determination of LDL receptor numbers in animals with markedly different concentrations of circulating LDL, conditions in which the use of endogenous ligand would be subject to significant errors.

scholarly journals A role for palmitoylation in the quality control, assembly and secretion of apolipoprotein B

2004 ◽  
Vol 377 (1) ◽  
pp. 121-130 ◽  
Author(s):  
Gonzalo L. VILAS ◽  
Luc G. BERTHIAUME
Keyword(s):  
Quality Control ◽  
Apolipoprotein B ◽  
Neutral Lipids ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Wild Type ◽  
Er Quality Control ◽  
Lipoprotein Particles ◽  
Secretion Efficiency

ApoB (apolipoprotein B)-containing lipoprotein particles, such as chylomicrons, very-low-density and low-density lipoprotein particles, transport triacylglycerol and cholesteryl esters in the bloodstream. A palmitoylation site was previously mapped to Cys-1085 in a functional truncated apoB variant (apoB-29) and abolished by mutagenesis. This Cys-1085Ser mutation resulted in secretion of smaller and denser lipoprotein particles containing 80% less cholesteryl ester and triacylglycerol than wild-type controls. We show that palmitoylation of apoB-29 occurs in the ER (endoplasmic reticulum), stimulates the ER–Golgi transport rate of apoB-29 almost 2-fold, doubles the secretion efficiency of wild-type apoB-29 in comparison with (Cys-1085Ser)apoB-29 and reduces significantly the association of wild-type apoB-29 with calnexin in comparison with (Cys-1085Ser)apoB-29. While non-palmitoylated apoB-29 co-localized extensively with constitutively secreted transferrin, wild-type apoB-29 did so only partially and was enriched in ER extensions. Our results suggest that palmitoylation of apoB regulates the biogenesis of nascent apoB-containing lipoprotein particles by concentrating apoB in a specialized ER compartment and by stimulating dissociation from constituents of the ER quality-control machinery. This reduced interaction would lead to a faster ER–Golgi transit time and a higher secretion efficiency of wild-type apoB-29. Palmitoylation could regulate the amount of apoB available for secretion of neutral lipids.

scholarly journals Reduced β-strand content in apoprotein B-100 in smaller and denser low-density lipoprotein subclasses as probed by Fourier-transform infrared spectroscopy

1997 ◽  
Vol 322 (3) ◽  
pp. 765-769 ◽  
Author(s):  
Fabio TANFANI ◽  
Tiziana GALEAZZI ◽  
Giovanna CURATOLA ◽  
Enrico BERTOLI ◽  
Gianna FERRETTI
Keyword(s):  
Fourier Transform ◽  
Secondary Structure ◽  
Apolipoprotein B ◽  
Gradient Centrifugation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Subclasses ◽  
Ldl Particles ◽  
Ldl Subfractions

The secondary structure of apolipoprotein B-100 in low-density lipoprotein (LDL) subfractions was analysed by Fourier-transform IR spectroscopy. LDLs were isolated in three density ranges by gradient centrifugation of human plasma from healthy volunteers. The spectra revealed differences in the lipid content and composition of the three LDL fractions. The secondary structure of apolipoprotein B-100 was the same in the two fractions corresponding to the large less-dense LDL particles, whereas a lower content of β-strands was found in the third fraction corresponding to the smaller denser LDL particles. Analysis of the spectroscopic data suggests that, in the same set of LDL subfractions, the particle size is probably the cause of the observed differences in apolipoprotein B-100 secondary structure.

scholarly journals Delayed Low Density Lipoprotein (LDL) Catabolism Despite a Functional Intact LDL-Apolipoprotein B Particle and LDL-Receptor in a Subject with Clinical Homozygous Familial Hypercholesterolemia

1998 ◽  
Vol 83 (6) ◽  
pp. 2167-2174 ◽  
Author(s):  
Hartmut H.-J. Schmidt ◽  
Manfred Stuhrmann ◽  
Robert Shamburek ◽  
C. Knud Schewe ◽  
Margit Ebhardt ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Apolipoprotein B ◽  
Receptor Gene ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Homozygous Familial Hypercholesterolemia ◽  
Ldl Catabolism ◽  
Normal Controls

We identified a 38-yr-old male patient with the clinical expression of homozygous familial hypercholesterolemia presenting as severe coronary artery disease, tendon and skin xanthomas, arcus lipoides, and joint pain. The genetic trait seems to be autosomal recessive. Interestingly, serum concentrations of cholesterol responded well to diet and statins. We had no evidence of an abnormal low density lipoprotein (LDL)-apolipoprotein B (apoB) particle, which was isolated from the patient using the U937 proliferation assay as a functional test of the LDL-binding capacity. The apoB 3500 and apoB 3531 defects were ruled out by PCR. In addition, we found no evidence for a defect within the LDL-receptor by skin fibroblast analysis, linkage analysis, single-strand conformational polymorphism and Southern blot screening across the entire LDL-receptor gene. The in vivo kinetics of radioiodinated LDL-apoB were evaluated in the proband and three normal controls, subsequently. The LDL-apoB isolated from the patient showed a normal catabolism, confirming an intact LDL particle. In contrast the fractional catabolic rate (d−1) of autologous LDL in the subject and the normal controls revealed a remarkable delayed catabolism of the patient’s LDL (0.15 vs. 0.33–0.43 d−1). In addition, the elevation of LDL-cholesterol in the patient resulted from an increased production rate with 22.8 mg/kg per day vs. 12.7–15.7 mg/kg per day. These data indicate that there is another catabolic defect beyond the apoB and LDL-receptor gene causing familial hypercholesterolemia.

Iron-catalyzed oxidation of Trp residues in low-density lipoprotein

2011 ◽  
Vol 392 (10) ◽  
pp. 859-867 ◽  
Author(s):  
Hsin-Hung Chen ◽  
Ching-Yi Chen ◽  
Lu-Ping Chow ◽  
Chu-Huang Chen ◽  
Yuan-Teh Lee ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Experimental Studies ◽  
Density Lipoprotein ◽  
Low Density ◽  
Iron Species ◽  
Diagnostic Biomarkers ◽  
Ldl Particles ◽  
Catalyzed Oxidation

Abstract The mechanisms of oxidation of low-density lipoproteins (LDLs) are not well defined, but epidemiological and experimental studies suggest that iron-catalyzed processes may contribute to atherogenesis. The aim of this study was to test the hypothesis that iron-catalyzed oxidations of LDLs in vitro produce diagnostic biomarkers of oxidation of the apolipoprotein that could be applied to studies in vivo. LDLs were oxidized in the presence of Fe2+, EDTA, and ascorbic acid for up to 40 h. Following delipidation and trypsin digestion, the peptides were separated by HPLC, with four peaks detected at 365 nm, whereas none were observed in peptides from unoxidized LDLs. The peptides were identified by MALDI-QTOF mass spectrometry as IVQILP(W+4) EQNEQVK, IYSL(W+4)EHSTK, FEGLQE(W+4)EGK, and YH(W+4)EHTGLTLR, with (W+4) rather than the W residues of the unoxidized protein. The mass gains (+4 increase in m/z in tryptophan, W) and absorbance at 365 nm indicate kynurenines, which were trypsin-releasable peptides that are on the surface of LDL particles. All four peptides thus characterized share the sequence of WE. The preferential oxidation of W residues in WE sequences suggest contributions from the C-proximate glutamate residues in chelation of the iron species, thereby influencing site selectivities of oxidation. These kynurenine-containing peptides might serve as biomarkers of iron-mediated oxidations in vivo.

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