Blockade of the α<sub>2</sub>‐Macroglobulin Receptor/Low‐Density‐Lipoprotein‐Receptor‐Related Protein on Rat Liver Parenchymal Cells by the 39‐kDa Receptor‐Associated Protein Leaves the Interaction of β‐Migrating very‐Low‐Density Lipoprotein with the Lipoprotein Remnant Receptor Unaffected

Ziere, Gijsbertus; Kaaden, M.E. van der; Vogelezang, C.J.M.; Boers, W.; Bihain, Bernard E.; Kuiper, Johan; Kruijt, J. Kar; Berkel, Theo J.C. Van

doi:10.1111/j.1432-1033.1996.0703r.x

Cited by 11 publications

(7 citation statements)

References 70 publications

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“…We found that a single dose (100 g/mL) of GST-RAP was unable to block DNA synthesis of Mv1Lu cells during an 18 h incubation. This was consistent with a report that RAP was no longer effective in blocking ␣ 2 M* association and degradation in cells after a Ͼ1 h incubation time, presumably due to efficient cellular binding and degradation of RAP under culture conditions (39). For this reason, Mv1Lu cells were incubated with various concentrations of IGFBP-3 and GST-RAP (100 g/mL) or the solvent vehicle, each (GST-RAP or the solvent vehicle) added to the culture medium hourly for 8 h. After further incubation for 10 h, DNA synthesis of the cells was determined.…”

Section: Rap Inhibits Binding Of Igfbp-3 and Tgf-␤ 1 To Cell Surface supporting

confidence: 93%

Cellular growth inhibition by IGFBP‐3 and TGF‐β₁requires LRP‐1

et al. 2003

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The type V TGF-beta receptor (TbetaR-V)/IGFBP-3 receptor mediates the IGF-independent growth inhibition induced by IGFBP-3. It also mediates the growth inhibitory response to TGF-beta1 in concert with other TGF-beta receptor types, and its loss may contribute to the malignant phenotype of human carcinoma cells. Here we demonstrate that TbetaR-V is identical to LRP-1/alpha2M receptor as shown by MALDI-TOF analysis of tryptic peptides of TbetaR-V purified from bovine liver. In addition, 125I-IGFBP-3 affinity-labeled TbetaR-V in Mv1Lu cells is immunoprecipitated by antibodies to LRP-1 and TbetaR-V. RAP, an LRP-1 antagonist, inhibits binding of 125I-TGF-beta1 and 125I-IGFBP-3 to TbetaR-V and diminishes IGFBP-3-induced growth inhibition in Mv1Lu cells. Absent or low levels of LRP-1, as with TbetaR-V, have been linked to the malignant phenotype of carcinoma cells. Mutagenized Mv1Lu cells selected for reduced expression of LRP-1 have an attenuated growth inhibitory response to TGF-beta1 and IGFBP-3. LRP-1-deficient mouse embryonic fibroblasts lack a growth inhibitory response to TGF-beta1 and IGFBP-3. On the other hand, stable transfection of H1299 human lung carcinoma cells with LRP-1 cDNA restores the growth inhibitory response. These results suggest that the LRP-1/TbetaR-V/IGFBP-3 receptor is required for the growth inhibitory response to IGFBP-3 and TGF-beta1.

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Section: Rap Inhibits Binding Of Igfbp-3 and Tgf-␤ 1 To Cell Surface supporting

confidence: 93%

Cellular growth inhibition by IGFBP‐3 and TGF‐β₁requires LRP‐1

et al. 2003

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“…Although the precise mechanism of the uptake of A␤⅐apoE complex observed here is uncertain, it is possible that other apoE receptors (e.g. low density lipoprotein receptor, which is known as the major receptor for apoE) (49) were involved; RAP might have failed to efficiently block the uptake of A␤⅐lipidated apoE complex because of the relatively low affinity of other apoE receptors for RAP compared with that of LRP1 (50).…”

Section: Discussionmentioning

confidence: 88%

The Low Density Lipoprotein Receptor-related Protein 1 Mediates Uptake of Amyloid β Peptides in an in Vitro Model of the Blood-Brain Barrier Cells

Yamada

Hashimoto

Yabuki

et al. 2008

Journal of Biological Chemistry

103

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The metabolism of amyloid ␤ peptide (A␤) in the brain is crucial to the pathogenesis of Alzheimer disease. A body of evidence suggests that A␤ is actively transported from brain parenchyma to blood across the blood-brain barrier (BBB), although the precise mechanism remains unclear. To unravel the cellular and molecular mechanism of A␤ transport across the BBB, we established a new in vitro model of the initial internalization step of A␤ transport using TR-BBB cells, a conditionally immortalized endothelial cell line from rat brain. We show that TR-BBB cells rapidly internalize A␤ through a receptor-mediated mechanism. We also provide evidence that A␤ internalization is mediated by LRP1 (low density lipoprotein receptor-related protein 1), since administration of LRP1 antagonist, receptorassociated protein, neutralizing antibody, or small interference RNAs all reduced A␤ uptake. Despite the requirement of LRP1-dependent internalization, A␤ does not directly bind to LRP1 in an in vitro binding assay. Unlike TR-BBB cells, mouse embryonic fibroblasts endogenously expressing functional LRP1 and exhibiting the authentic LRP1-mediated endocytosis (e.g. of tissue plasminogen activator) did not show rapid A␤ uptake. Based on these data, we propose that the rapid LRP1-dependent internalization of A␤ occurs under the BBB-specific cellular context and that TR-BBB is a useful tool for analyzing the molecular mechanism of the rapid transport of A␤ across BBB. Aggregation and deposition of amyloid ␤-peptide (A␤)2 in the brain are crucial events in the pathogenesis of Alzheimer disease (AD) (1). A␤ is produced from ␤-amyloid precursor protein through sequential proteolytic cleavages by ␤-and ␥-secretases. Missense mutations as well as duplication of the ␤-amyloid precursor protein gene have been identified in pedigrees of early onset familial AD (2-4), some of which have been shown to alter the ␤-amyloid precursor protein processing in such a way as to increase the level of A␤, especially that of the more aggregable species A␤42, leading to formation of A␤ fibrils (5-7). Cognitive deficits in transgenic mice overexpressing familial AD mutant form ␤-amyloid precursor protein, as well as alteration in synaptic plasticity and synapse loss induced by A␤ oligomers implicate aggregated species of A␤ in the neuronal dysfunction and death in AD brains (8 -10).A␤, secreted from neurons in the brain, is thought to be catabolized by specific proteases (e.g. NEP and insulin-degrading enzyme) (11, 12); phagocytotic cells in brains (i.e. microglia and astrocytes) (13, 14) take up and clear soluble or aggregated A␤. Notably, in vivo observations that A␤ injected into rodent brains is rapidly effluxed from brains (15, 16) suggest the presence of a novel pathway for A␤ clearance across the blood-brain barrier (BBB). The BBB is considered as a three-cell archetype composed of brain microvascular endothelial cells (BMECs), astrocytes, and supporting pericytes. It does not normally allow a free exchange of macromolecules between brain and blood, ...

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“…It is generally accepted, however, that for the initial liver recognition of remnants, the so-called "capture step," additional systems are needed. The initial sequestration step was suggested to involve heparan sulfate proteoglycans (5,12), the lipolysis-stimulated receptor (13)(14)(15), a TG-rich lipoprotein receptor (16,17), the asialoglycoprotein receptor (18), LPL (19), and/or hepatic lipase (20), while we also provided evidence for a specific remnant receptor (21)(22)(23) to function as an initial recognition site for remnants. However, the removal pathways of chylomicrons and their remnants remain complex, and the precise mechanism of recognition is still unclear and under debate (1-3).…”

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confidence: 82%

Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

Out¹,

Kruijt²,

Rensen³

et al. 2004

Journal of Biological Chemistry

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The function of scavenger receptor class B type I (SR-BI) in mediating the selective uptake of high density lipoprotein (HDL) cholesterol esters is well established. However, the potential role of SR-BI in chylomicron and chylomicron remnant metabolism is largely unknown. In the present investigation, we report that the cell association of 160 nm-sized triglyceride-rich chylomicronlike emulsion particles to freshly isolated hepatocytes from SR-BI-deficient mice is greatly reduced (>70%), as compared with wild-type littermate mice. Competition experiments show that the association of emulsion particles with isolated hepatocytes is efficiently competed for (>70%) by the well established SR-BI ligands, HDL and oxidized low density lipoprotein (LDL), whereas LDL is ineffective. Upon injection into SR-BI-deficient mice the hepatic association of emulsion particles is markedly decreased (ϳ80%) as compared with wild-type mice. The relevance of these findings for in vivo chylomicron (remnant) metabolism was further evaluated by studying the effect of SR-BI deficiency on the intragastric fat load-induced postprandial triglyceride response. The postprandial triglyceride response is 2-fold higher in SR-BI-deficient mice as compared with wild-type littermates (area-under-the-curve 39.6 ؎ 1.2 versus 21.1 ؎ 3.6; p < 0.005), with a 4-fold increased accumulation of chylomicron (remnant)-associated triglycerides in plasma at 6 h after intragastric fat load. We conclude that SR-BI is important in facilitating chylomicron (remnant) metabolism and might function as an initial recognition site for chylomicron remnants whereby the subsequent internalization can be exerted by additional receptor systems like the LDL receptor and LDL receptor-related protein. Chylomicrons are triglyceride (TG)1 -rich lipoproteins that transport dietary lipids from the intestine to the liver. Upon entering the circulation, chylomicrons are converted to remnants by the TG-hydrolyzing action of lipoprotein lipase (LPL) and the acquisition of apolipoproteins (apo) such as apoE. Chylomicron remnants are subsequently taken up by the liver by an apoE-mediated process (reviewed in Refs. 1-3). The essential role of apoE in remnant clearance was indicated by the accumulation of remnants in apoE-deficient mice (4). It has been suggested that several apoE-dependent recognition sites contribute to the removal of remnants, including the low-density lipoprotein (apoB and -E) receptor (LDLr) (4 -9), and the LDLr-related protein/␣ 2 -macroglobulin receptor (LRP) (8, 10, 11). It is generally accepted, however, that for the initial liver recognition of remnants, the so-called "capture step," additional systems are needed. The initial sequestration step was suggested to involve heparan sulfate proteoglycans (5, 12), the lipolysis-stimulated receptor (13-15), a TG-rich lipoprotein receptor (16, 17), the asialoglycoprotein receptor (18), LPL (19), and/or hepatic lipase (20), while we also provided evidence for a specific remnant receptor (21-23) to function as an initial re...

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Cited by 11 publications

References 70 publications

Cellular growth inhibition by IGFBP‐3 and TGF‐β₁requires LRP‐1

Cellular growth inhibition by IGFBP‐3 and TGF‐β₁requires LRP‐1

The Low Density Lipoprotein Receptor-related Protein 1 Mediates Uptake of Amyloid β Peptides in an in Vitro Model of the Blood-Brain Barrier Cells

Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

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Cited by 11 publications

References 70 publications

Cellular growth inhibition by IGFBP‐3 and TGF‐β1requires LRP‐1

Cellular growth inhibition by IGFBP‐3 and TGF‐β1requires LRP‐1

The Low Density Lipoprotein Receptor-related Protein 1 Mediates Uptake of Amyloid β Peptides in an in Vitro Model of the Blood-Brain Barrier Cells

Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

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Cellular growth inhibition by IGFBP‐3 and TGF‐β₁requires LRP‐1

Cellular growth inhibition by IGFBP‐3 and TGF‐β₁requires LRP‐1