The Experts below are selected from a list of 25236 Experts worldwide ranked by ideXlab platform
Joachim Herz - One of the best experts on this subject based on the ideXlab platform.
-
Low-Density LipoProtein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis
EBioMedicine, 2016Co-Authors: Yinyuan Ding, Xunde Xian, William L. Holland, Shirling Tsai, Joachim HerzAbstract:Low-density LipoProtein Receptor-Related Protein-1 (LRP1) is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β) trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO) predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2) translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density LipoProtein (VLDL) triglyceride secretion.
-
The low-density-LipoProtein Receptor-Related Protein (LRP) is processed by furin in vivo and in vitro.
Biochemical Journal, 1996Co-Authors: Thomas E. Willnow, Joan M. Moehring, Noel M. Inocencio, Thomas J. Moehring, Joachim HerzAbstract:The low-density-LipoProtein Receptor-Related Protein (LRP) is a multifunctional receptor involved in the clearance of a large number of diverse ligands, including proteases, protease-inhibitor complexes and LipoProteins. The mature receptor is composed of a 515 kDa and a 85 kDa subunit generated by proteolytic cleavage from a 600 kDa precursor polypeptide in a trans-Golgi compartment. Proteolytic processing occurs C-terminal to the tetrabasic amino acid sequence RHRR, a consensus recognition site for precursor processing endoproteases or convertases. In this study we have identified furin, a subtilisin-type protease, to be necessary for efficient processing of LRP in cells. Furin-deficient RPE.40 cells exhibited an impaired processing of endogenous LRP and of a recombinant soluble form of the receptor containing the processing site. The processing defect in RPE.40 cells could be complemented by expression of furin from a transfected cDNA in cultured cells and by purified furin in vitro. The impaired maturation of LRP in RPE.40 cells did not affect its intracellular transport, and correlated with a slight but consistent reduction in the endocytosis of LRP-specific ligands. These data suggest that proteolytic processing of LRP by furin is not necessary for intracellular trafficking but might be required for normal receptor activity.
-
39-kDa Protein modulates binding of ligands to low density LipoProtein Receptor-Related Protein/alpha 2-macroglobulin receptor.
The Journal of biological chemistry, 1991Co-Authors: Joachim Herz, Dudley K Strickland, Joseph L. Goldstein, Michael S. BrownAbstract:A 39-kDa Protein of unknown function has previously been reported to copurify with the low density LipoProtein Receptor-Related Protein (LRP)/alpha 2-macroglobulin receptor. In this study we demonstrate that a recombinant 39-kDa fusion Protein can reversibly bind to the 515-kDa subunit of the LRP/alpha 2-macroglobulin receptor. This interaction inhibits the binding and uptake of the receptor's two known ligands: 1) beta-migrating very low density LipoProteins activated by enrichment with apoProtein E and 2) alpha 2-macroglobulin activated by incubation with plasma proteases or methylamine. A potential in vivo role of the 39-kDa Protein is to modulate the uptake of apoE-enriched LipoProteins and activated alpha 2-macroglobulin in hepatic and extrahepatic tissues.
Patrick L. Mcgeer - One of the best experts on this subject based on the ideXlab platform.
-
Subcellular localization of the low density LipoProtein Receptor-Related Protein (α2-macroglobulin receptor) in human brain
Brain Research, 1995Co-Authors: Ikuo Tooyama, T. Kawamata, Haruhiko Akiyama, Hiroshi Kimura, Søren K. Moestrup, Jørgen Gliemann, Akinori Matsuo, Patrick L. McgeerAbstract:The subcellular localization of the α2-macroglobulin receptor, also known as the low density LipoProtein Receptor-Related Protein (LRP), was studied in postmortem human brain tissue by light and electron microscopic immunocytochemistry. A specific monoclonal antibody (A2MR2) against the extracellular α-chain of the molecule was utilized. Light microscopically, LRP was detected strongly in neurons, weakly in some glial cells and discontinuously along capillary membranes. At the electron microscopic level, positive reaction products were found to be associated with plasma membranes, ribosomes, lysosomes and lipofuscin granules of neurons, glial cells and pericytes. The results suggest that LRP may have a function, particularly in neurons, of receptor-mediated endocytosis with subsequent lysosomal uptake and degradation of ligands such a α2-macroglobulin Proteinase complexes and apoLipoProtein E.
-
Subcellular localization of the low density LipoProtein Receptor-Related Protein (alpha 2-macroglobulin receptor) in human brain.
Brain research, 1995Co-Authors: Ikuo Tooyama, T. Kawamata, Haruhiko Akiyama, Hiroshi Kimura, Søren K. Moestrup, Jørgen Gliemann, Akinori Matsuo, Patrick L. McgeerAbstract:The subcellular localization of the alpha 2-macroglobulin receptor, also known as the low density LipoProtein Receptor-Related Protein (LRP), was studied in postmortem human brain tissue by light and electron microscopic immunocytochemistry. A specific monoclonal antibody (A2MR2) against the extracellular alpha-chain of the molecule was utilized. Light microscopically, LRP was detected strongly in neurons, weakly in some glial cells and discontinuously along capillary membranes. At the electron microscopic level, positive reaction products were found to be associated with plasma membranes, ribosomes, lysosomes and lipofuscin granules of neurons, glial cells and pericytes. The results suggest that LRP may have a function, particularly in neurons, of receptor-mediated endocytosis with subsequent lysosomal uptake and degradation of ligands such as alpha 2-macroglobulin Proteinase complexes and apoLipoProtein E.
Philippe Amouyel - One of the best experts on this subject based on the ideXlab platform.
-
Low-density LipoProtein Receptor-Related Protein 8 gene polymorphisms and dementia
Neurobiology of aging, 2007Co-Authors: Nicole Helbecque, Dominique Cottel, Philippe AmouyelAbstract:The sole known genetic risk factor for sporadic Alzheimer's disease (AD) is the gene encoding apoLipoProtein E (APOE), but the underlying mechanism is still under debate. One hypothesis relies on an interaction between APOE and its receptors. Previous studies have shown association of LDL Receptor-Related Protein (LRP1) with AD and we previously reported a modulation by LRP1 of the risk of AD conferred by the -499A>G promoter polymorphism of the MAPK8IP1, a gene encoding Islet-brain-1 (IB1), the human counterpart of c-Jun NH(2) terminal kinase interacting Protein-1 (JIP-1). Here we tested in two independent population samples a possible impact of another receptor for APOE, namely the low-density LipoProtein Receptor-Related Protein 8 (LRP8), on the risk of dementia. Our results did not reveal any direct impact of a LRP8 coding (Arg952Gln) mutation on the risk of AD. However, this polymorphism increased the risk of AD conferred by the MAPK8IP1 G allele.
-
Association between the low density LipoProtein Receptor-Related Protein (LRP) and Alzheimer's disease
Neuroscience letters, 1997Co-Authors: Fabienne Wavrant-devrieze, Philippe Amouyel, Jordi Pérez-tur, Jean-charles Lambert, Bernard Frigard, Florence Pasquier, André Delacourte, John Hardy, Marie-christine Chartier-harlinAbstract:Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people. It usually occurs after 65 years old (late-onset AD). The epsilon4 allele of apoLipoProtein E (APOE) gene is a risk factor which contributes about 50% of the genetic risk for this form of the disease. The low density LipoProtein Receptor-Related Protein (LRP) is a major receptor for APOE which is found in the senile plaques of AD brains. This makes it a good candidate gene for the disease. There is a polymorphism in the region upstream of the LRP gene that has been associated with AD in an American population. We examined this polymorphism by restriction fragment length polymorphism analysis in a French population with sporadic late-onset AD. In the previous report, a significant increase of the 87 bp allele was found in the AD cases; however, in our population, we observed a significant decrease with this same allele of the LRP gene. The possible reasons for this discrepancy, linkage disequilibrium or statistical anomaly, are discussed.
Søren K. Moestrup - One of the best experts on this subject based on the ideXlab platform.
-
Specific binding of alpha-macroglobulin to complement-type repeat CR4 of the low-density LipoProtein Receptor-Related Protein.
Biochemistry, 2000Co-Authors: Olav M. Andersen, Christian Jacobsen, Søren K. Moestrup, Peter Christensen, Lisa Lystbæk Christensen, Michael Etzerodt, Hans Christian ThøgersenAbstract:The low-density LipoProtein Receptor-Related Protein (LRP) is a large surface receptor that mediates binding and internalization of a large number of structurally and functionally unrelated ligands. The ligand binding sites are located in clusters of complement-type repeats (CR), where the general absence of mutual binding competition suggests that different ligands map to distinct sites. Binding of α2-macroglobulin−protease complexes to the LRP is mediated by the receptor binding domain (RBD) of α2-macroglobulin (α2M). To determine the major binding epitope(s) in the LRP, we generated a complete set of tandem CR Proteins spanning the second cluster of CR domains, and identified a binding site for α2M in the N-terminal part of the cluster comprising CR3−CR6, using ligand blotting and surface plasmon resonance (SPR) analysis. The specific site involved in α2M recognition resides in the fourth CR domain, CR4, whereas another site is identified in CR5. An acidic epitope in CR4 is identified as important for ...
-
Subcellular localization of the low density LipoProtein Receptor-Related Protein (α2-macroglobulin receptor) in human brain
Brain Research, 1995Co-Authors: Ikuo Tooyama, T. Kawamata, Haruhiko Akiyama, Hiroshi Kimura, Søren K. Moestrup, Jørgen Gliemann, Akinori Matsuo, Patrick L. McgeerAbstract:The subcellular localization of the α2-macroglobulin receptor, also known as the low density LipoProtein Receptor-Related Protein (LRP), was studied in postmortem human brain tissue by light and electron microscopic immunocytochemistry. A specific monoclonal antibody (A2MR2) against the extracellular α-chain of the molecule was utilized. Light microscopically, LRP was detected strongly in neurons, weakly in some glial cells and discontinuously along capillary membranes. At the electron microscopic level, positive reaction products were found to be associated with plasma membranes, ribosomes, lysosomes and lipofuscin granules of neurons, glial cells and pericytes. The results suggest that LRP may have a function, particularly in neurons, of receptor-mediated endocytosis with subsequent lysosomal uptake and degradation of ligands such a α2-macroglobulin Proteinase complexes and apoLipoProtein E.
-
Subcellular localization of the low density LipoProtein Receptor-Related Protein (alpha 2-macroglobulin receptor) in human brain.
Brain research, 1995Co-Authors: Ikuo Tooyama, T. Kawamata, Haruhiko Akiyama, Hiroshi Kimura, Søren K. Moestrup, Jørgen Gliemann, Akinori Matsuo, Patrick L. McgeerAbstract:The subcellular localization of the alpha 2-macroglobulin receptor, also known as the low density LipoProtein Receptor-Related Protein (LRP), was studied in postmortem human brain tissue by light and electron microscopic immunocytochemistry. A specific monoclonal antibody (A2MR2) against the extracellular alpha-chain of the molecule was utilized. Light microscopically, LRP was detected strongly in neurons, weakly in some glial cells and discontinuously along capillary membranes. At the electron microscopic level, positive reaction products were found to be associated with plasma membranes, ribosomes, lysosomes and lipofuscin granules of neurons, glial cells and pericytes. The results suggest that LRP may have a function, particularly in neurons, of receptor-mediated endocytosis with subsequent lysosomal uptake and degradation of ligands such as alpha 2-macroglobulin Proteinase complexes and apoLipoProtein E.
-
Distribution of the α_2-macroglobulin receptor/low density LipoProtein Receptor-Related Protein in human tissues
Cell and Tissue Research, 1992Co-Authors: Søren K. Moestrup, Jørgen Gliemann, Gorm PallesenAbstract:The hepatic α_1-macroglobulin receptor (α_2MR)/low density LipoProtein Receptor-Related Protein (LRP) binds and endocytoses α_2-macroglobulin-Proteinase complexes in plasma. In addition, it binds LipoProteins, a novel 40 kDa Protein, and complexes between plasminogen activators and plasminogen activator inhibitor type-1. This study shows, for the first time, the tissue distribution of α_2MR/LRP as determined by immunohistochemistry with specific monoclonal antibodies. The analysis revealed α_2MR/LRP-expression in a restricted spectrum of cell types, including neurons and astrocytes in the central nervous system, epithelial cells of the gastrointestinal tract, smooth muscle cells, fibroblasts, Leydig cells in testis, granulosa cells in ovary, and dendritic interstitial cells of kidney. Monocytederived cells displayed marked α_2MR/LRP expression in the phagocytes of liver, lung and lymphoid tissues, but no or low expression in antigen-presenting cells including Langerhans' cells of the skin. The high abundance of α_2MR/LRP in certain cell types of most organs suggests two main routes for α_2MR/LRP ligand clearance: (1) systemic removal in liver of circulating ligands, and (2) non-hepatic interstitial removal in different organs, including the brain.
Dudley K Strickland - One of the best experts on this subject based on the ideXlab platform.
-
Low-Density LipoProtein Receptor–Related Protein-1 Role in the Regulation of Vascular Integrity
Arteriosclerosis thrombosis and vascular biology, 2014Co-Authors: Dudley K Strickland, Patricia Cunfer, Selen C. MuratogluAbstract:Low-density LipoProtein Receptor-Related Protein-1 (LRP1) is a large endocytic and signaling receptor that is widely expressed. In the liver, LRP1 plays an important role in regulating the plasma levels of blood coagulation factor VIII (fVIII) by mediating its uptake and subsequent degradation. fVIII is a key plasma Protein that is deficient in hemophilia A and circulates in complex with von Willebrand factor. Because von Willebrand factor blocks binding of fVIII to LRP1, questions remain on the molecular mechanisms by which LRP1 removes fVIII from the circulation. LRP1 also regulates cell surface levels of tissue factor, a component of the extrinsic blood coagulation pathway. This occurs when tissue factor pathway inhibitor bridges the fVII/tissue factor complex to LRP1, resulting in rapid LRP1-mediated internalization and downregulation of coagulant activity. In the vasculature LRP1 also plays protective role from the development of aneurysms. Mice in which the lrp1 gene is selectively deleted in vascular smooth muscle cells develop a phenotype similar to the progression of aneurysm formation in human patient, revealing that these mice are ideal for investigating molecular mechanisms associated with aneurysm formation. Studies suggest that LRP1 protects against elastin fiber fragmentation by reducing excess protease activity in the vessel wall. These proteases include high-temperature requirement factor A1, matrix metalloProteinase 2, matrix metalloProteinase-9, and membrane associated type 1-matrix metalloProteinase. In addition, LRP1 regulates matrix deposition, in part, by modulating levels of connective tissue growth factor. Defining pathways modulated by LRP1 that lead to aneurysm formation and defining its role in thrombosis may allow for more effective intervention in patients.
-
low density LipoProtein receptor related Protein 1 lrp1 regulates thrombospondin 2 tsp2 enhancement of notch3 signaling
Journal of Biological Chemistry, 2010Co-Authors: He Meng, Xiaojie Zhang, Soo Jung Lee, Dudley K Strickland, Daniel A Lawrence, Michael M WangAbstract:Intracellular trafficking of Notch and Notch ligands modulates signaling, suggesting that choreography of ligand and receptor translocation is essential for optimal Notch activity. Indeed, a major model for Notch signaling posits that Notch trans-endocytosis into the ligand-expressing (signal sending) cell is a key driving force for Notch signal transduction. The extracellular Protein thrombospondin-2 (TSP2) enhances Notch signaling and binds to both Jagged1 and Notch3 ectodomains, potentially bridging two essential extracellular components of Notch signaling. We investigated the role of low density LipoProtein Receptor-Related Protein-1 (LRP1), a TSP2 receptor, in the regulation of Notch3 signaling. TSP2 potentiation of Notch is blocked by the receptor-associated Protein (an inhibitor of low density LipoProtein Receptor-Related Protein function) and requires LRP1 expression in the signal-sending cell. TSP2 stimulates Notch3 endocytosis into wild type fibroblasts but not LRP1-deficient fibroblasts. Finally, recombinant Notch3 and Jagged1 interact with the LRP1 85-kDa B-chain, a subunit that lacks known ligand binding function. Our data suggest that LRP1 and TSP2 stimulate Notch activity by driving trans-endocytosis of the Notch ectodomain into the signal-sending cell and demonstrate a novel, non-cell autonomous function of LRP1 in cell-cell signaling.
-
Microglial low-density LipoProtein Receptor-Related Protein 1 modulates c-Jun N-terminal kinase activation
Journal of Neuroimmunology, 2009Co-Authors: Ana Pocivavsek, Dudley K Strickland, Irina Mikhailenko, G. William RebeckAbstract:ApoLipoProtein E (apoE)-induced activation of low-density LipoProtein receptor (LDL) family members reduces inflammatory responses by suppressing c-Jun N-terminal kinase (JNK) activation. We aimed to identify which specific receptor family member mediates the effect of apoE on inflammation in primary cultures of microglia. Low-density LipoProtein Receptor-Related Protein 1 (LRP1)-deficient (LRP1 −/−) microglia were derived from mice using tissue-specific loxP/Cre recombination. Using a peptide formed from the receptor-binding region of apoE (EP), we found that LRP1 mediates the effects of apoE on microglial inflammation. Microglial LRP1 was also essential for EP to suppress JNK activation induced by lipopolysaccharide.
-
Low density LipoProtein receptor–related Protein is a calreticulin coreceptor that signals focal adhesion disassembly
The Journal of cell biology, 2003Co-Authors: Anthony Wayne Orr, Dudley K Strickland, Claudio E. Pedraza, Manuel A. Pallero, Carrie A. Elzie, Silvia M. Goicoechea, Joanne E. Murphy-ullrichAbstract:Thrombospondin (TSP) signals focal adhesion disassembly (the intermediate adhesive state) through interactions with cell surface calreticulin (CRT). TSP or a peptide (hep I) of the active site induces focal adhesion disassembly through binding to CRT, which activates phosphoinositide 3-kinase (PI3K) and extracellular signal–related kinase (ERK) through Gαi2 Proteins. Because CRT is not a transmembrane Protein, it is likely that CRT signals as part of a coreceptor complex. We now show that low density LipoProtein receptor–related Protein (LRP) mediates focal adhesion disassembly initiated by TSP binding to CRT. LRP antagonists (antibodies, receptor-associated Protein) block hep I/TSP-induced focal adhesion disassembly. LRP is necessary for TSP/hep I signaling because TSP/hep I is unable to stimulate focal adhesion disassembly or ERK or PI3K signaling in fibroblasts deficient in LRP. LRP is important in TSP–CRT signaling, as shown by the ability of hep I to stimulate association of Gαi2 with LRP. The isolated Proteins LRP and CRT interact, and LRP and CRT are associated with hep I in molecular complexes extracted from cells. These data establish a mechanism of cell surface CRT signaling through its coreceptor, LRP, and suggest a novel function for LRP in regulating cell adhesion.
-
Role of the Low-density LipoProtein Receptor–Related Protein in β-Amyloid Metabolism and Alzheimer Disease
Archives of neurology, 2000Co-Authors: Bradley T. Hyman, Dudley K Strickland, G. William RebeckAbstract:Deposition of beta-amyloid (A beta), a metabolite of approximately 4 kd of the amyloid precursor Protein, is a critical pathological feature in Alzheimer disease. We postulate that deposition reflects an imbalance of A beta synthesis and clearance. Several pathways that impact A beta converge on a single receptor molecule, the low-density LipoProtein Receptor-Related Protein (LRP). This multifunctional receptor is the major neuronal receptor both for apoLipoProtein E (apoE, Protein; APOE, gene) and for alpha2-macroglobulin (alpha2M, Protein; A2M, gene), and it mediates clearance of apoE/A beta and alpha2M/A beta complexes. The LRP also interacts with the amyloid precursor Protein itself. In this review, we highlight data that support a role for LRP in A beta metabolism and hypothesize that LRP therefore plays a critical role in Alzheimer disease.