scholarly journals Predominantly Increased Triglyceride-rich Lipoproteins Induced by Dietary Cholesterol Promoted Atherosclerosis Formation in LDL Receptor Knockout Golden Hamster

2021 ◽  
Author(s):  
Yuhui Wang ◽  
Xiao Lin ◽  
Ping Ma ◽  
Chun Yang ◽  
Jinjie Wang ◽  
...  
Keyword(s):  
Golden Hamster ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Ldl Receptor ◽  
Experimental System ◽  
Lipid Uptake ◽  
Knock Out ◽  
Ezetimibe Treatment ◽  
Vascular Adhesion

Abstract Epidemiological investigation showed that triglyceride is an independent risk factor of cardiovascular diseases, but it is difficult to distinguish the effects of different lipoproteins by an experimental system in vivo, the role of triglyceride-rich lipoproteins (TRLs) in atherosclerosis have not been fully understood. Here we found LDL receptor knock-out (LDLR−/−) hamsters have special characteristics of lipid profile for investigating effects of TRLs. Mixed hyperlipidemia in LDLR−/− hamsters after high cholesterol and high fat (HCHF) diet were marked by increasing of chylomicrons, VLDL and their remnants, but not LDL. Ezetimibe treatment significantly decreased these large particles containing ApoB and ApoE without affecting LDL, leading to the dramatic reduction of plasma cholesterol and triglycerides. 40 days of HCHF diet feeding accelerated aortic atherosclerosis accompanied severe fatty liver, and ezetimibe treatment inhibited their development. Also, TRLs lowering inhibited the expression of vascular adhesion factors and lipid uptake of macrophage. Our results suggest that golden hamster is a proper model for studying hypertriglyceridemia related diseases. In LDLR−/− hamster, TRLs showed independent atherogenicity by triggering inflammatory response of endothelial cells and the formation of foam cells from macrophages. And these TRLs clearance is mediated by LDL receptor. TRLs would be an important therapeutic target for atherosclerotic development with postprandial hyperlipidemia.

Dietary cholesterol: from physiology to cardiovascular risk

2011 ◽  
Vol 106 (1) ◽  
pp. 6-14 ◽  
Author(s):  
Jean-Michel Lecerf ◽  
Michel de Lorgeril
Keyword(s):  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Ldl Receptor ◽  
Epidemiological Data ◽  
Cholesterol Absorption ◽  
Cholesterol Content ◽  
Biological Data ◽  
Related Protein ◽  
Cvd Risk ◽  
Nutritional Factors

Dietary cholesterol comes exclusively from animal sources, thus it is naturally present in our diet and tissues. It is an important component of cell membranes and a precursor of bile acids, steroid hormones and vitamin D. Contrary to phytosterols (originated from plants), cholesterol is synthesised in the human body in order to maintain a stable pool when dietary intake is low. Given the necessity for cholesterol, very effective intestinal uptake mechanisms and enterohepatic bile acid and cholesterol reabsorption cycles exist; conversely, phytosterols are poorly absorbed and, indeed, rapidly excreted. Dietary cholesterol content does not significantly influence plasma cholesterol values, which are regulated by different genetic and nutritional factors that influence cholesterol absorption or synthesis. Some subjects are hyper-absorbers and others are hyper-responders, which implies new therapeutic issues. Epidemiological data do not support a link between dietary cholesterol and CVD. Recent biological data concerning the effect of dietary cholesterol on LDL receptor-related protein may explain the complexity of the effect of cholesterol on CVD risk.

Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions

2007 ◽  
Vol 293 (4) ◽  
pp. H2394-H2402 ◽  
Author(s):  
Chantal M. C. Dupasquier ◽  
Elena Dibrov ◽  
Annette L. Kneesh ◽  
Paul K. M. Cheung ◽  
Kaitlin G. Y. Lee ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Plasma Cholesterol ◽  
Saturated Fatty Acids ◽  
Dietary Cholesterol ◽  
Ldl Receptor ◽  
Plaque Formation ◽  
Nuclear Antigen ◽  
Aortic Tissue ◽  
Deficient Mouse ◽  
Anti Inflammatory

Dietary flaxseed has been shown to have potent antiatherogenic effects in rabbits. The purpose of the present study was to investigate the antiatherogenic capacity of flaxseed in an animal model that more closely represents the human atherosclerotic condition, the LDL receptor-deficient mouse (LDLrKO), and to identify the cellular mechanisms for these effects. LDLrKO mice were administered a regular diet (RG), a 10% flaxseed-supplemented diet (FX), or an atherogenic diet containing 2% cholesterol alone (CH) or supplemented with 10% flaxseed (CF), 5% flaxseed (CF5), 1% flaxseed (CF1), or 5% coconut oil (CS) for 24 wk. LDLrKO mice fed a cholesterol-supplemented diet exhibited a rise in plasma cholesterol without a change in triglycerides and an increase in atherosclerotic plaque formation. The CS mice exhibited elevated levels of plasma cholesterol, triglycerides, and saturated fatty acids and an increase in plaque development. Supplementation of the cholesterol-enriched diet with 10% (wt/wt) ground flaxseed lowered plasma cholesterol and saturated fatty acids, increased plasma ALA, and inhibited plaque formation in the aorta and aortic sinus compared with mice fed a diet supplemented with only dietary cholesterol. The expression of proliferating cell nuclear antigen (PCNA) and the inflammatory markers IL-6, mac-3, and VCAM-1 was increased in aortic tissue from CH and CS mice. This expression was significantly reduced or normalized when flaxseed was included in the diet. Our results demonstrate that dietary flaxseed can inhibit atherosclerosis in the LDLrKO mouse through a reduction of circulating cholesterol levels and, at a cellular level, via antiproliferative and anti-inflammatory actions.

2288Oxidized LDL/CD36/PPARg circuitry is a trigger of adipogenesis in arrhythmogenic cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Stadiotti ◽  
E Sommariva ◽  
M Casella ◽  
V Catto ◽  
A Dello Russo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Accumulation ◽  
Foam Cell ◽  
Plasma Cholesterol ◽  
Foam Cell Formation ◽  
Arrhythmogenic Cardiomyopathy ◽  
Knock Out ◽  
Fatty Replacement

Abstract Background Arrhythmogenic Cardiomyopathy (ACM) is a genetic condition hallmarked by ventricular fibro-fatty replacement and arrhythmias. Cardiac mesenchymal stromal cells (C-MSC) differentiate into adipocytes in ACM hearts, through the activation of PPARγ, caused by ACM mutations (e.g. PKP2). The clinical phenotype of ACM is variable for poorly understood reasons. The only recognized cofactor is physical exercise, which is known to increases oxidative stress. An accepted marker of exercise-induced oxidative stress is 13HODE, a component of oxLDL and direct activator of PPARγ. In macrophages, during foam cell formation, 13HODE creates a feed-forward loop increasing both PPARγ and the oxLDL receptor CD36, resulting in fat accumulation. Purpose To investigate oxLDL effects on ACM adipogenesis and to dissect the involved pathways. Methods We analyzed plasmas (n=42) and ventricular tissues (n=4) of ACM patients and matched healthy controls (HC). For in vitro experiments, ACM and HC C-MSC (n=10) have been used, while in vivo experiments have been conducted in heterozygous Pkp2 knock-out mice (Pkp2+/−; n=10). Results We observed higher plasma oxLDL in ACM patients compared to HC (ACM 246.70±55.89 vs HC 102.5±17.95ng/ml; p=0.019). oxLDL levels also discriminate between ACM patients with overt phenotype and their unaffected relatives carriers of the same causative mutations (p=0.03). We observed higher oxidative stress (MDA intensity 40.87±11.76 fold; p=0.015) and CD36 levels (14.72±2.10 fold; p=0.0007) in ACM ventricular tissue, compared to HC. In basal conditions, ACM C-MSC showed greater oxidative stress (MDA intensity 8.83±2.78 fold p=0.017) and higher expression of PPARγ (1.47±0.14 fold; p=0.009) compared to HC C-MSC. The adipogenic stimulation led to a parallel increase of CD36 and lipid accumulation, mainly in ACM C-MSC (slopes statistically different p=0.016). OxLDL and 13HODE administration increased lipid accumulation in ACM C-MSC (ORO staining ACM vs ACM+oxLDL p=0.01; ACM vs ACM+13HODE p=0.014). On the contrary, the antioxidant N-Acetylcysteine (NAC) prevented lipid accumulation in ACM C-MSC (ORO staining ACM+13HODE vs ACM+13HODE+NAC p=0.0009). Through CD36 silencing of ACM C-MSC, we obtained a significantly lower lipid accumulation than non-silenced cells (ORO staining 0.35±0.10 fold; p=0.003). Pkp2+/− mice do not spontaneously accumulate adipocytes in the heart, however Pkp2+/− C-MSC are more prone to lipid accumulation in vitro than WT cells (p=0.007). Accordingly, mice have low plasma oxLDL and cardiac oxidative stress. By increasing plasma cholesterol and oxidative stress through high fat diet, we observed fibro-fatty substitution in Pkp2+/− hearts (p=0.046). Figure 1 Conclusions These findings reveal a modulatory role of oxidized lipids in ACM adipogenesis at a cellular, tissue and clinical level, enlightening novel targets for pharmacological strategies to prevent adipogenic substitution and consequent ACM clinical phenotypes. Acknowledgement/Funding Telethon Foundation; Italian Ministry of Health

scholarly journals Genomic and Transcriptomic Analysis of Hypercholesterolemic Rabbits: Progress and Perspectives

2018 ◽  
Vol 19 (11) ◽  
pp. 3512 ◽  
Author(s):  
Jianglin Fan ◽  
Yajie Chen ◽  
Haizhao Yan ◽  
Baoning Liu ◽  
Yanli Wang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Plasma Cholesterol ◽  
Dietary Cholesterol ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Chow Diet ◽  
Low Density ◽  
Elevated Plasma ◽  
Wild Type ◽  
Very Low Density Lipoproteins

Rabbits (Oryctolagus cuniculus) are one of the most widely used animal models for the study of human lipid metabolism and atherosclerosis because they are more sensitive to a cholesterol diet than other experimental animals such as rodents. Currently, two hypercholesterolemic rabbit models are frequently used for atherosclerosis studies. One is a cholesterol-fed wild-type rabbit and the other is the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is genetically deficient in low density lipoprotein (LDL) receptor function. Wild-type rabbits can be easily induced to develop severe hypercholesterolemia with a cholesterol-rich diet due to the marked increase in hepatically and intestinally derived remnant lipoproteins, called β-very low density lipoproteins (VLDL), which are rich in cholesteryl esters. WHHL rabbits are characterized by elevated plasma LDL levels on a standard chow diet, which resembles human familial hypercholesterolemia. Therefore, both rabbit models develop aortic and coronary atherosclerosis, but the elevated plasma cholesterol levels are caused by completely different mechanisms. In addition, cholesterol-fed rabbits but not WHHL rabbits exhibit different degrees of hepatosteatosis. Recently, we along with others have shown that there are many differentially expressed genes in the atherosclerotic lesions and livers of cholesterol-fed rabbits that are either significantly up- or down-regulated, compared with those in normal rabbits, including genes involved in the regulation of inflammation and lipid metabolism. Therefore, dietary cholesterol plays an important role not only in hypercholesterolemia and atherosclerosis but also in hepatosteatosis. In this review, we make an overview of the recent progress in genomic and transcriptomic analyses of hypercholesterolemic rabbits. These transcriptomic profiling data should provide novel insight into the relationship between hypercholesterolemia and atherosclerosis or hepatic dysfunction caused by dietary cholesterol.

PEGylation or Polysialylation Reduces FVIII Binding to LRP Resulting in Prolonged Half-Life in Murine Models.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3150-3150 ◽  
Author(s):  
Hanspeter Rottensteiner ◽  
Peter L. Turecek ◽  
Rona Pendu ◽  
Alexander B. Meijer ◽  
Peter Lenting ◽  
...  
Keyword(s):  
Half Life ◽  
Low Density Lipoprotein ◽  
Polysialic Acid ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Receptor Interaction ◽  
Knock Out ◽  
Lysine Residues ◽  
Knock Out Mice

Abstract The low-density lipoprotein (LDL)-receptor-related protein 1 (LRP1) binds FVIII and is involved in the in vivo clearance and regulation of FVIII plasma levels. The significance of LRP in the regulation of FVIII metabolism has been demonstrated both in conditional LRP1 knock-out mice resulting in increased endogenous levels and prolonged survival of FVIII and by blocking LRP in hemophilic mice leading to prolonged half-life of infused human FVIII. In the current study we investigated whether random chemical modification of lysine residues of recombinant FVIII with branched polyethylene glycol (PEG) or polysialic acid (PSA) polymers interferes with LRP interaction. The modified FVIII variants, both of which gave rise to an increased half-life in mouse PK studies, were compared with rFVIII for binding to LRP1 by surface plasmon resonance (SPR) methodology. The typical binding of FVIII to LRP1 was more reduced by polysialylation than by PEGylation. To further delineate the region within the binding domain of LRP1 that recognizes FVIII, the isolated clusters II and IV were analyzed for FVIII interaction in an ELISA-based assay. Interestingly, FVIII bound to both clusters with comparable affinity, indicating that the CR of cluster II and IV have the same ligand-binding specificity. The PEGylated FVIII showed a reduced binding to both immobilized clusters, but also for the modified protein there was no clear preference for one of the two domains. The specificity of FVIII binding to cluster II was further analyzed by competition experiments. Increasing concentrations of cluster II diminished the signal for both FVIII and the PEGylated variant with an IC50 of about 1 mM. Also heparin had a weak competitive effect, suggesting that this inherently anticoagulant compound could contribute to increase the half-life of FVIII. While the LRP1 binding site in the light chain of FVIII is accessible also in non-activated FVIII, that within the heavy chain of FVIII is only exposed after its activation by thrombin. It was therefore additionally tested whether limited thrombin treatment would increase the affinity of modified FVIII for LRP1. While a 40% increase in binding of rFVIII was observed, this was not the case for modified FVIII, indicating that the attached polymers also interfere with this interaction site of FVIII. The presented data suggest that drastically reduced binding to LRP1 contributes to the increase in half-life of modified FVIII. Because polysialylation and PEGylation both involve surface-exposed lysine residues, the findings further support the view that lysine-containing surface loops in FVIII are key elements in the interaction with its clearance receptor LRP. The in vivo significance of inhibiting the FVIII receptor interaction was demonstrated in VWF-FVIII double knock-out mice. While FVIII, co-administered with VWF, had a half-life of 2.1 h, infusion of PEG-rFVIII alone in these animals lacking both VWF and FVIII led to a dramatic increase of FVIII half-life to 8.3 h. The prolonged half-life of PEG-rFVIII in the absence of VWF suggests that PEG-rFVIII interferes with clearance mechanisms and may substitute for the necessary VWF-FVIII complex formation and several of the physiological VWF-FVIII protective mechanisms. Hence, PEG-rFVIII has potential as the treatment of choice in patients with type Normandy von Willebrand’s disease.

Abstract 429: Structural Stability of Streptococcal Serum Opacity Factor

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Corina Rosales ◽  
Baiba K Gillard ◽  
Dedipya Yelamanchili ◽  
Antonio M Gotto ◽  
Henry J Pownall
Keyword(s):  
Disulfide Bonds ◽  
Plasma Cholesterol ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cholesterol Levels ◽  
Serum Opacity Factor ◽  
Apo E ◽  
Plasma High Density

Despite its putative cardioprotective qualities, raising plasma high density lipoprotein-cholesterol (HDL-C) levels via pharmacologic means has failed to add protection against atherosclerosis, particularly when used as co-therapy with a statin. Two scenarios argue against the raising-plasma-HDL-is-better hypothesis and suggest that enhancing the final RCT step, hepatic cholesterol disposal, is a better cardioprotective strategy. First, probucol prevents CVD events and increases survival in humans and reduces CVD in SR-BI/apo E DKO mice. Despite its anti atherogenic properties, probucol lowers plasma HDL-C levels. Second, SR-BI over expressing vs. WT mice have lower plasma HDL-C but less atherosclerosis whereas the converse is true in SR-BI KO mice, suggesting that increasing HDL-C disposal is a rational cardioprotective strategy. One possible agent for therapeutic development is streptococcal serum opacity factor (SOF), a 100 kDa protein that clouds human serum via a novel HDL-targeting mechanism. SOF diverts HDL-CE to the LDL receptor and to bile acid secretion in vitro and in vivo, increases plasma HDL-C clearance in mice in an apo E-, LDLR-dependent mechanism thereby increasing hepatic CE uptake and reducing plasma cholesterol levels. SOF is active at 10 -14 M. Given its novel mechanism and potent reduction of plasma cholesterol levels in mice, we studied the structure and stability of SOF using its activity as a marker of its integrity versus several physicochemical challenges—extremes of pH, the denaturant, guanidinium chloride, heat, and ionic strength. SOF was highly resistant to all of these challenges. SOF has only one cysteine so it cannot be stabilized by internal disulfide bonds. Thus, SOF is an unusually stable protein that undergoes reversible unfolding-folding when challenged with a variety of physicochemical perturbants. These studies have helped us identify optimal conditions for crystallizing SOF for X-ray structure analysis.

Abstract 5: Sortilin Regulates Hepatic VLDL Secretion and LDL Uptake in a Lysosome-Dependent Manner

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Alanna Strong ◽  
Qiurong Ding ◽  
Andrew Edmondson ◽  
Sumeet Khetarpal ◽  
Carlos Morales ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Plasma Cholesterol ◽  
Association Studies ◽  
Ldl Receptor ◽  
Genome Wide Association Studies ◽  
Dependent Manner ◽  
Ldl Particles ◽  
Vldl Secretion ◽  
Ldl Uptake

Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome and plasma membrane to lysosome protein trafficking. Genome wide association studies for lipid traits have identified the 1p13 locus harboring the SORT1 gene as strongly associated both with plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) risk in humans. Adeno-associated virus (AAV)-mediated hepatic sortilin overexpression in LDL receptor deficient mice reduced plasma cholesterol by 30% at two weeks ( n = 6 mice per group, P = 0.02), with a concomitant reduction in LDL-C. In vivo VLDL production studies demonstrated a 50% reduction in the VLDL triglyceride secretion rate ( P = 0.007) and a 50% reduction in apoB secretion ( P = 0.02) with sortilin overexpression. In vivo LDL turnover studies demonstrated a 3-fold increase in the LDL fractional catabolic rate (FCR) with sortilin overexpression ( n = 6 mice per group, P = 0.00002). Sortilin deficiency both alone and on an LDL receptor deficient background led to a 40% and 50% reduction in FCR ( n = 6 mice per group, P = 0.002 and P = 0.01). The effect of sortilin on both VLDL secretion and LDL turnover is dependent on the ability of sortilin to traffic to the lysosome, as sortilin mutants that cannot traffic to the lysosome do not affect VLDL secretion or LDL uptake in vivo or in vitro . Surface plasmon reasonance demonstrated a high affinity interaction between sortilin and the apoB in LDL particles at physiological pH with a K d of ∼2 nM, and this affinity virtually disappears at the acidic lysosomal pH. In sum, these data are consistent with a model in which sortilin binds apoB-containing lipoprotein particles in the Golgi apparatus and at the plasma membrane and traffics them to the endolysosomal compartment for degradation, thereby reducing VLDL secretion and facilitating LDL uptake, explaining the strong association of hepatic sortilin overexpression in humans with reduced plasma cholesterol.

scholarly journals Off-Target Effect of Lovastatin Disrupts Dietary Lipid Uptake and Dissemination through Pro-Drug Inhibition of the Mesenteric Lymphatic Smooth Muscle Cell Contractile Apparatus

2021 ◽  
Vol 22 (21) ◽  
pp. 11756
Author(s):  
Matthew Stephens ◽  
Simon Roizes ◽  
Pierre-Yves von der Weid
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Cell Function ◽  
Structural Characteristics ◽  
Dietary Cholesterol ◽  
Dietary Lipid ◽  
Lipid Absorption ◽  
Lipid Uptake

Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic effects. However, the effect of these drugs on lymphatic vascular smooth muscle cell function, and by proxy dietary cholesterol uptake, by the intestinal lymphatic network has not been investigated. Several of the most widely prescribed statins (Atorvastatin, Pravastatin, Lovastatin, and Simvastatin) were tested for their in-situ effects on smooth muscle contractility in rat mesenteric collecting lymphatic vessels. Lovastatin and Simvastatin had a concentration-dependent effect of initially increasing vessel contraction frequency before flatlining the vessel, a phenomenon which was found to be a lactone-ring dependent phenomenon and could be ameliorated through use of Lovastatin- or Simvastatin-hydroxyacid (HA). Simvastatin treatment further resulted in mitochondrial depolymerization within primary-isolated rat lymphatic smooth muscle cells (LMCs) while Lovastatin was found to be acting in a mitochondrial-independent manner, increasing the function of RhoKinase. Lovastatin’s effect on RhoKinase was investigated through pharmacological testing and in vitro analysis of increased MLC and MYPT1 phosphorylation within primary isolated LMCs. Finally, acute in vivo treatment of rats with Lovastatin, but not Lovastatin-HA, resulted in a significantly decreased dietary lipid absorption in vivo through induced disfunction of mesenteric lymph uptake and trafficking.

scholarly journals A LewisX Glycoprotein Screen Identifies the Low Density Lipoprotein Receptor-related Protein 1 (LRP1) as a Modulator of Oligodendrogenesis in Mice

2013 ◽  
Vol 288 (23) ◽  
pp. 16538-16545 ◽  
Author(s):  
Eva Hennen ◽  
Dina Safina ◽  
Ute Haussmann ◽  
Philipp Wörsdörfer ◽  
Frank Edenhofer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Carrier Proteins ◽  
Systematic Analysis ◽  
Knock Out

In the developing and adult CNS multipotent neural stem cells reside in distinct niches. Specific carbohydrates and glycoproteins are expressed in these niche microenvironments which are important regulators of stem cell maintenance and differentiation fate. LewisX (LeX), also known as stage-specific embryonic antigen-1 or CD15, is a defined carbohydrate moiety expressed in niche microenvironments of the developing and adult CNS. LeX-glycans are involved in stem cell proliferation, migration, and stemness. A few LeX carrier proteins are known, but a systematic analysis of the targets of LeX glycosylation in vivo has not been performed so far. Using LeX glycosylation as a biomarker we aimed to discover new glycoproteins with a potential functional relevance for CNS development. By immunoaffinity chromatography we enriched LeX glycoproteins from embryonic and postnatal mouse brains and used one-dimensional nLC-ESI-MS/MS for their identification. We could validate phosphacan, tenascin-C, and L1-CAM as major LeX carrier proteins present in vivo. Furthermore, we identified LRP1, a member of the LDL receptor family, as a new LeX carrier protein expressed by mouse neural stem cells. Surprisingly, little is known about LRP1 function for neural stem cells. Thus, we generated Lrp1 knock-out neural stem cells by Cre-mediated recombination and investigated their properties. Here, we provide first evidence that LRP1 is necessary for the differentiation of neural stem cells toward oligodendrocytes. However, this function is independent of LeX glycosylation.

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