Characteristics of chylomicron remnant uptake into rat liver

Huettinger, Manfred; Retzek, Helmut; Eder, M.; Goldenberg, Hans

doi:10.1016/s0009-9120(88)80093-6

Cited by 75 publications

(53 citation statements)

References 24 publications

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“…Within the description of miscellaneous ligands of LRP/~2MR also in vitro binding of Lf was demonstrated [1]. Together with our first description of the potency of Lf to inhibit chylomicron remnant uptake in vivo [4] these data prompted us to more directly investigate a possible physiologic importance of the binding of Lf to LRP/c~2MR. In a first step we here confirm the identity of LRP/a2MR with the sole Lf-binding protein found in endosomes by ligand-and immunoblotting.…”

Section: **Present Addressmentioning

confidence: 89%

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Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α₂‐macroglobulin receptor and transport to endosomes

et al. 1995

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LDL receptor related protein (LRP) is a ubiquitously expressed cell surface receptor that binds, at least in vitro, a plethora of ligands among them c~2-macroglobulin and lactoferrin (Lf). The function of LRP in internalisation and distribution of ligands within cellular metabolism is still unclear. We here investigated by combined ligand-and immunoblotting the participation of LRP/a2MR and its associated protein (RAP) in receptor mediated endocytosis of Lf into rat liver. We found LRP highly enriched in sucrose density gradient fractions around density I.I0 g/ml, previously characterised as endosomal fractions. RAP was concentrated in distinct fractions around density 1.14 g/ml. This separation of RAP from LRPIa2MR is physiologically meaningful as RAP avidly binds to LRPIa2MR and by that shuts off aH ligand binding function. In endosomal fractions we found one single binding protein for ~2Sl-labelled Lf. With a specific anti LRPla2MR antibody and ligand blotting with 125I-labelled RAP this endosomal Lf binding site was verified to be LRP/azMR. Endosomes did not bind labelled Lf when prepared from rats that received an intravenous injection of Lf (20 mg per animal) 20 rain prior to preparation. Surprisingly we immunodetected Lf in these endosomes at a position around 600 kDa, comigrating with LRP/ c~2MR. We determined Lf binding to be optimal at pH 5.8, what led us to suggest the existence of a very stable LF-LRP/c~2MR complex in endosomes. These data support the idea of effective binding of Lf at pH as found in inflamed tissue environment where Lf is reported to be involved in leukocyte mediated inflammation regulation.

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Section: **Present Addressmentioning

confidence: 89%

“…Whether uptake into liver is mediated in part by a sui generis receptor remains a matter of dispute. It has been reported that binding of Lf to cells is mediated via several mechanisms, but internalisation is likely to be mediated by a receptor mediated process [1][2][3][4][5]. A candidate receptor for this might be LRP/a2MR.…”

Section: Introductionmentioning

confidence: 99%

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α₂‐macroglobulin receptor and transport to endosomes

et al. 1995

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“…One possibility is that uptake of GV-LDL occurs through a multistep process beginning with an initial binding to cell-surface heparan sulfate proteoglycans (HSPG), followed by their uptake into cells by a receptor-mediated process that utilizes members of the low density lipoprotein receptor family (34 -36). Several studies have shown that LRP binds apoE-enriched particles (50,51) and that the clearance of apoE-containing particles, such as chylomicron remnants and ␤-very low density lipoprotein, is inhibited by lactoferrin (38,52,53), a molecule that also binds to LRP (37). We tested the possible involvement of LRP in proteoglycan-mediated uptake of GV-LDL using lactoferrin.…”

Section: Discussionmentioning

confidence: 99%

Group V Secretory Phospholipase A2-modified Low Density Lipoprotein Promotes Foam Cell Formation by a SR-A- and CD36-independent Process That Involves Cellular Proteoglycans

Boyanovsky

Westhuyzen

Webb

2005

Journal of Biological Chemistry

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Accumulating evidence indicates that secretory phospholipase A 2 (sPLA 2 ) enzymes promote atherogenic processes. We have previously showed the presence of Group V sPLA 2 (GV sPLA 2 ) in human and mouse atherosclerotic lesions, its hydrolysis of low density lipoprotein (LDL) particles, and the ability of GV sPLA 2 -modified LDL (GV-LDL) to induce macrophage foam cell formation in vitro. The goal of this study was to investigate the mechanisms involved in macrophage uptake of GV-LDL. Peritoneal macrophages from C57BL/6 mice (wild type (WT)), C57BL/6 mice deficient in LDL receptor (LDLR ؊/؊ ), or SR-A and CD36 (DKO) were treated with control LDL, GV-LDL, oxidized LDL (ox-LDL) or LDL aggregated by vortexing (vx-LDL). As expected, ox-LDL induced significantly more cholesterol ester accumulation in WT and LDLR ؊/؊ compared with DKO macrophages. In contrast, there was no difference in the accumulation of GV-LDL or vx-LDL in the three cell types. 125 I-ox-LDL exhibited high affinity, saturable binding to WT cells that was significantly reduced in DKO cells. Vx-LDL and GV-LDL showed low affinity, non-saturable binding that was similar for both cell types, and significantly higher compared with control LDL. GV-LDL degradation in WT and DKO cells was similar. Analyses by confocal microscopy indicated a distinct intracellular distribution of Alexa-568-labeled GV-LDL and Alexa-488-labeled ox-LDL. Uptake of GV-LDL (but not ox-LDL or vx-LDL) was significantly reduced in cells preincubated with heparin or NaClO 3 , suggesting a role for proteoglycans in GV-LDL uptake. Our data point to a physiological modification of LDL that has the potential to promote macrophage foam cell formation independent of scavenger receptors.A critical event in early atherogenesis is the formation of lipid-laden macrophages ("foam cells") (1-4). According to the "response-to-retention" hypothesis (5), conditions leading to enhanced LDL 2 entrapment in the subendothelium trigger this process. Once retained in the vessel wall, LDL undergoes various modifications in both protein and phospholipid (PL) moieties that promote retention and lead to enhanced macrophage uptake. Several types of modifications of LDL, such as oxidation (6 -8), depletion of sphingomyelin by secretory sphingomyelinase (9), hydrolysis of glycero-PLs by sPLA 2 enzymes (10 -12), and aggregation (13-18) have been implicated in lipid accumulation in the vessel wall.The sPLA 2 family comprises a group of enzymes that hydrolyze the acyl-ester bond at the 2 position (sn-2) of glycero-PLs. Of the 10 sPLA 2 isozymes that have been described in mammals, three members (Group IIA, Group V, and Group X) have been detected in human and/or mouse atherosclerotic lesions (10,11,19). Accumulating evidence indicates that sPLA 2 hydrolysis of LDL-PL results in structural alterations of the particles that promote lipid accumulation in the vessel wall and enhances macrophage uptake. Hydrolysis of LDL by sPLA 2 in vitro results in an increased affinity for proteoglycans, which would be expected to incre...

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“…Lactoferrin (aa [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] CAVS QPETKCFQRNMRKI/R yoelii CS, apoE, and lactoferrin. Boldface italics indicate amino acid residues of CS protein required for binding to HSPGs (22).…”

Section: Rklrkrllrdaedlqkrla Vmentioning

confidence: 99%

“…protein (LRP) (12). Lactoferrin also binds to HSPGs and LRP (12)(13)(14), and competes with remnant lipoproteins for hepatic clearance from the circulation and for internalization by hepatocytes (15,16).…”

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Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

Sinnis

Willnow

Briones

et al. 1996

The Journal of Experimental Medicine

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SummaryRemnants oflipoproteins, intestinal chylomicrons, and very low density lipoproteins (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs), and that their subsequent internalization into hepatocytes is mediated by members of the LDLreceptor gene family. Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein (CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs. Lactoferrin, a protein with antibacterial properties found in breast milk and neutrophil granules, is also rapidly cleared from the circulation by hepatocytes, and can inhibit the hepatic uptake of lipoprotein remnants. Here we provide evidence that sporozoites, lactoferrin, and remnant lipoproteins are cleared from the blood by similar mechanisms. CS, lactoferrin, and remnant lipoproteins compete in vitro and in vivo for binding sites on liver cells. The relevance of this binding event for sporozoite infectivity is highlighted by our demonstration that apoliprotein E-enriched [3-VLDL and lactoferrin inhibit sporozoite invasion of HepG2 cells. In addition, malaria sporozoites are less infective in LDL-receptor knockout (LDLR-/-) mice maintained on a high fat diet, as compared with littermates maintained on a normal diet. We conclude that the clearance oflipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane.

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Characteristics of chylomicron remnant uptake into rat liver

Cited by 75 publications

References 24 publications

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α₂‐macroglobulin receptor and transport to endosomes

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α₂‐macroglobulin receptor and transport to endosomes

Group V Secretory Phospholipase A2-modified Low Density Lipoprotein Promotes Foam Cell Formation by a SR-A- and CD36-independent Process That Involves Cellular Proteoglycans

Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

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Characteristics of chylomicron remnant uptake into rat liver

Cited by 75 publications

References 24 publications

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α2‐macroglobulin receptor and transport to endosomes

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α2‐macroglobulin receptor and transport to endosomes

Group V Secretory Phospholipase A2-modified Low Density Lipoprotein Promotes Foam Cell Formation by a SR-A- and CD36-independent Process That Involves Cellular Proteoglycans

Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

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Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α₂‐macroglobulin receptor and transport to endosomes

Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/α₂‐macroglobulin receptor and transport to endosomes