scholarly journals Platelet factor 4 regulates megakaryopoiesis through low-density lipoprotein receptor–related protein 1 (LRP1) on megakaryocytes

Blood ◽  
2009 ◽  
Vol 114 (11) ◽  
pp. 2290-2298 ◽  
Author(s):  
Michele P. Lambert ◽  
Yuhuan Wang ◽  
Khalil H. Bdeir ◽  
Yvonne Nguyen ◽  
M. Anna Kowalska ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Colony Growth ◽  
Platelet Factor 4 ◽  
Negative Regulator ◽  
Low Density ◽  
Related Protein ◽  
Platelet Factor

Abstract Platelet factor 4 (PF4) is a negative regulator of megakaryopoiesis, but its mechanism of action had not been addressed. Low-density lipoprotein (LDL) receptor–related protein-1 (LRP1) has been shown to mediate endothelial cell responses to PF4 and so we tested this receptor's importance in PF4's role in megakaryopoiesis. We found that LRP1 is absent from megakaryocyte-erythrocyte progenitor cells, is maximally present on large, polyploidy megakaryocytes, and near absent on platelets. Blocking LRP1 with either receptor-associated protein (RAP), an antagonist of LDL family member receptors, or specific anti-LRP1 antibodies reversed the inhibition of megakaryocyte colony growth by PF4. In addition, using shRNA to reduce LRP1 expression was able to restore megakaryocyte colony formation in bone marrow isolated from human PF4-overexpressing mice (hPF4High). Further, shRNA knockdown of LRP1 expression was able to limit the effects of PF4 on megakaryopoiesis. Finally, infusion of RAP into hPF4High mice was able to increase baseline platelet counts without affecting other lineages, suggesting that this mechanism is important in vivo. These studies extend our understanding of PF4's negative paracrine effect in megakaryopoiesis and its potential clinical implications as well as provide insights into the biology of LRP1, which is transiently expressed during megakaryopoiesis.

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 The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein

2007 ◽  
Vol 402 (1) ◽  
pp. 17-23 ◽  
Author(s):  
David R. Taylor ◽  
Nigel M. Hooper
Keyword(s):  
Prion Protein ◽  
Low Density Lipoprotein ◽  
Neuronal Cells ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Cellular Prion Protein ◽  
Low Density ◽  
Related Protein ◽  
Density Lipoprotein Receptor

PrPC (cellular prion protein) is located at the surface of neuronal cells in detergent-insoluble lipid rafts, yet is internalized by clathrin-dependent endocytosis. As PrPC is glycosyl-phosphatidylinositol-anchored, it requires a transmembrane adaptor protein to connect it to the clathrin endocytosis machinery. Using receptor-associated protein and small interfering RNA against particular LDL (low-density lipoprotein) family members, in combination with immunofluorescence microscopy and surface biotinylation assays, we show that the transmembrane LRP1 (LDL receptor-related protein 1) is required for the Cu2+-mediated endocytosis of PrPC in neuronal cells. We show also that another LRP1 ligand that can cause neurodegenerative disease, the Alzheimer's amyloid precursor protein, does not modulate the endocytosis of PrPC.

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 Low-density lipoprotein receptor-related protein 1 (LRP1) is a negative regulator of oligodendrocyte progenitor cell differentiation in the adult mouse brain

2020 ◽  
Author(s):  
Loic Auderset ◽  
Kimberley A Pitman ◽  
Carlie L Cullen ◽  
Renee E Pepper ◽  
Bruce V Taylor ◽  
...  
Keyword(s):  
Adult Mouse ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Negative Regulator ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Related Protein ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

AbstractLow-density lipoprotein receptor-related protein 1 (LRP1) is a large, endocytic cell surface receptor that is highly expressed by oligodendrocyte progenitor cells (OPCs), and LRP1 expression is rapidly downregulated as OPCs differentiate into oligodendrocytes (OLs). We report that the conditional deletion of Lrp1 from adult mouse OPCs (Pdgfrα-CreER :: Lrp1fl/fl) increases the number of new myelinating OLs added to brain, but that each new cell elaborates a normal quantity of myelin. OPC proliferation is also elevated following Lrp1 deletion in vivo, however, this is likely to be a secondary, homeostatic response to increased OPC differentiation, as our in vitro experiments show that LRP1 is a direct negative regulator of OPC differentiation, not proliferation. Deleting Lrp1 from adult OPCs also enhances remyelination, as cuprizone-induced lesions are smaller in Lrp1-deleted mice, and parenchymal OPCs produce a larger number of mature OLs. These data suggest that the selective blockade of LRP1 function on adult OPCs may enhance myelin repair in demyelinating diseases, such as multiple sclerosis.

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