Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor‐related protein/<i>α</i><sub>2</sub>‐macroglobulin receptor and transport to endosomes

Meilinger, Melinda; Haumer, Markus; Szakmary, Kati A.; Steinböck, Ferdinand; Scheiber, Barbara; Goldenberg, Hans; Huettinger, Manfred

doi:10.1016/0014-5793(95)00082-k

Cited by 63 publications

(41 citation statements)

References 45 publications

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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%

“…One is that proteoglycan binding of GV-LDL may be followed by uptake via a receptor-mediated process that utilizes the LDL receptorrelated protein (LRP), as has been shown for apoE-enriched chylomicron remnants (34 -36). To investigate this possibility, macrophages were incubated with GV-LDL in the presence of lactoferrin (5 mg/ml), which binds to LRP (37) and inhibits uptake of ␤-very low density lipoprotein and chylomicron remnants (38,39). Our results show that addition of lactoferrin has no effect on CE accumulation by macrophages (Fig.…”

Section: Gv-ldl Uptake By Macrophages Ismentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Gv-ldl Uptake By Macrophages Ismentioning

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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“…27 Many of these receptors have not yet been fully characterized or cloned, but lactoferrin was able to bind in a reversible, saturable, and specific manner to all these cell types and tissues. Among the putative lactoferrin receptors are the low-density lipoprotein receptor-related proteins-1 and -2 (LRP1 and LRP2) [28][29][30][31] which are multi-ligand members of the LRP family of endocytic receptors. 32 Binding of lactoferrin to LRP1 and LRP2 was initially demonstrated during investigation of the inhibitory effect of lactoferrin on the hepatic clearance of chylomicron remnants.…”

Section: Mechanisms Of Action In Osteoblastsmentioning

confidence: 99%

Lactoferrin - A Novel Bone Growth Factor

Naot¹,

Grey²,

Reid³

et al. 2005

Clinical Medicine & Research

148

101

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Lactoferrin is an iron-binding glycoprotein that belongs to the transferrin family. It is present in breast milk, in epithelial secretions, and in the secondary granules of neutrophils. In healthy subjects lactoferrin circulates at concentrations of 2-7 x 10 -6 g/ml. Lactoferrin is a pleiotropic factor with potent antimicrobial and immunomodulatory activities. Recently, we have shown that lactoferrin can also promote bone growth. At physiological concentrations, lactoferrin potently stimulates the proliferation and differentiation of primary osteoblasts and also acts as a survival factor inhibiting apoptosis induced by serum withdrawal. Lactoferrin also affects osteoclast formation and, in murine bone marrow culture, lactoferrin potently inhibits osteoclastogenesis. In vivo, local injection of lactoferrin above the hemicalvaria of adult mice results in substantial increases in the dynamic histomorphometric indices of bone formation and bone area.The mitogenic effect of lactoferrin in osteoblast-like cells is mediated mainly through LRP1, a member of the family of low-density lipoprotein receptor-related proteins that are primarily known as endocytic receptors. Using confocal laser scanning microscopy, we demonstrated that fluorescently labeled lactoferrin is endocytosed and can be visualized in the cytoplasm of primary osteoblastic cells. Lactoferrin also induces activation of p42/44 MAPK signaling in primary osteoblasts, but the two pathways seem to operate independently as activation of MAPK signaling, but not endocytosis, is necessary for the mitogenic effect of lactoferrin. We conclude that lactoferrin may have a physiological role in bone growth and healing, and a potential therapeutic role as an anabolic factor in osteoporosis.

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“…23 After synthesis, LRP is cleaved into 515-kDa (␣-chain) and 85-kDa (␤-chain) subunits. 24 LRP has been shown to act as an endocytosis-mediating receptor for several ligands, including lactoferrin, 25,26 thrombospondin, 27 protease-anti-protease complexes, 28 plasma lipoproteins such as apoE-enriched VLDL, 29,30 lipoprotein lipase and lipoprotein lipase-triglyceride-rich lipoprotein complexes, [31][32][33] and Lp(a). 34 Therefore, the aim of the present study was to demonstrate whether LRP was responsible for the binding and internalization of agLDLs in VSMCs.…”

mentioning

confidence: 99%

LDL Receptor–Related Protein Mediates Uptake of Aggregated LDL in Human Vascular Smooth Muscle Cells

Llorente‐Cortés

Martínez-González

Badimon

2000

ATVB

136

154

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Abstract-Foam cell formation is a key event in the onset and progression of atherosclerotic lesions. We have previously reported that internalization of aggregated low density lipoproteins (agLDLs) by vascular smooth muscle cells (VSMCs) produces cholesteryl ester (CE) accumulation in these cells. The aim of this study was to analyze whether the low density lipoprotein receptor-related protein (LRP) mediates the uptake of agLDL by VSMCs. First, immunocytochemistry and fluorescence microscopic analysis with the use of anti-LRP antibodies indicated that there was a high expression of LRP in VSMCs. Confocal microscopic analysis with the use of agLDLs labeled with fluorochrome 1,1Ј-dioctadecyl-3,3,3Ј,3Ј-tetramethylindocarbocyanine and anti-LRP antibodies showed the colocalization of agLDL and LRP.The second approach was to analyze the effect of LRP ligands on agLDL internalization; lactoferrin strongly inhibited CE accumulation from agLDLs (85.0Ϯ5.7% at 25 g/mL) by impairing agLDL binding. Coincubation of agLDL with anti-LRP antibodies decreased in a dose-dependent manner agLDL-derived CE accumulation (from 20% at 12.5 g/mL to 80% at 50 g/mL). The third approach was to evaluate whether antisense LRP oligodeoxynucleotides were able to block agLDL internalization. Treatment of VSMCs with 5 mol/L antisense LRP oligodeoxynucleotides reduced agLDL-derived CE accumulation by 84Ϯ2%. In conclusion, these results from immunologic, biochemical, and molecular interventions demonstrate that LRP mediates the binding and internalization of agLDL in human VSMCs. Because LRP is highly expressed in VSMCs and the uptake of 1 LDL aggregate amounts to the deposition of several hundreds of LDL particles, the uptake of agLDL through LRP could have a crucial role for lipid deposition in VSMCs. O ne of the main events in the atherogenic process is the accumulation of lipids, mainly cholesteryl esters (CEs). 1,2 Vascular smooth muscle cells (VSMCs) synthesize proteoglycans, extracellular matrix components involved in the focal deposition of cholesterol-rich particles. 3,4 The uptake of matrix-retained lipoproteins by VSMCs and macrophages produces CE accumulation and leads to foam cell formation. Macrophages become foam cells through the uptake of diversely modified LDLs, whereas the aggregation of LDLs seems to be a key condition for lipid accumulation in VSMCs. [5][6][7] Recently, we have shown that accumulation of CEs in VSMCs from in vitro-aggregated LDL (agLDL) is dependent on agLDL concentration and the degree of aggregation. 8 AgLDLs obtained by vortexing LDL in vitro share structural characteristics with LDL aggregates present in atherosclerotic lesions. 9 -11 In macrophages, phagocytosis and/or scavenger receptors mediate cholesterol accumulation from different types of modified LDL. [12][13][14][15][16] In human lesions, scavenger receptors are present at high levels in macrophages but not in VSMCs. 17,18 VSMCs express scavenger receptors only after stimulation with certain growth factors, 19,20 and a direct involvement of these...

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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

Cited by 63 publications

References 45 publications

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

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

Lactoferrin - A Novel Bone Growth Factor

LDL Receptor–Related Protein Mediates Uptake of Aggregated LDL in Human Vascular Smooth Muscle Cells

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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

Cited by 63 publications

References 45 publications

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

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

Lactoferrin - A Novel Bone Growth Factor

LDL Receptor–Related Protein Mediates Uptake of Aggregated LDL in Human Vascular Smooth Muscle Cells

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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