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[PMID]:28867180
[Au] Autor:Aizawa S; Hoki M; Yamamuro Y
[Ad] Endereço:Laboratory of Animal Genetics and Physiology, Department of Animal Science, College of Bioresource Sciences, Nihon University, Japan. Electronic address: aizawa.shu@nihon-u.ac.jp.
[Ti] Título:Lactoferrin promotes autophagy via AMP-activated protein kinase activation through low-density lipoprotein receptor-related protein 1.
[So] Source:Biochem Biophys Res Commun;493(1):509-513, 2017 Nov 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lactoferrin (LF) is a multifunctional, iron-binding glycoprotein in mammalian secretions, such as breast milk, and has several beneficial effects for human health. However, how these effects are exerted at the cellular level is still largely unknown. In this study, we investigated the effects of LF on autophagy activity in NIH/3T3 mouse fibroblasts. LF from bovine milk was found to increase LC3-I to LC3-II conversion and LC3-positive cytosolic punctate structures because of increased autophagy flux. Knockdown of the putative LF receptor low-density receptor-related protein 1 (LRP1) completely abolished LC3 conversion in cells by LF treatment. Moreover, exposure to LF increased the phosphorylation levels of AMPK in cells, and treatment of dorsomorphin, a pharmacological inhibitor of AMPK signaling, attenuated LC3 conversion by LF. Therefore, we concluded that the beneficial effects of LF might be due to an increase of autophagy activity via AMPK signaling through the LRP1 receptor. These findings provide a novel insight into the physiological role of LF for the maintenance of cellular and tissue homeostasis.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo
Autofagia/efeitos dos fármacos
Autofagia/fisiologia
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo
Lactoferrina/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Ativação Enzimática/efeitos dos fármacos
Camundongos
Células NIH 3T3
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LDL-Receptor Related Protein-Associated Protein); EC 2.7.11.31 (AMP-Activated Protein Kinases); EC 3.4.21.- (Lactoferrin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:27931217
[Au] Autor:Yang L; Liu CC; Zheng H; Kanekiyo T; Atagi Y; Jia L; Wang D; N'songo A; Can D; Xu H; Chen XF; Bu G
[Ad] Endereço:Institute of Neuroscience, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College, Xiamen University, Xiamen, 361102, China.
[Ti] Título:LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways.
[So] Source:J Neuroinflammation;13(1):304, 2016 Dec 08.
[Is] ISSN:1742-2094
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Neuroinflammation is characterized by microglial activation and the increased levels of cytokines and chemokines in the central nervous system (CNS). Recent evidence has implicated both beneficial and toxic roles of microglia when over-activated upon nerve injury or in neurodegenerative diseases, including Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for apolipoprotein E (apoE) and amyloid-ß (Aß), which play critical roles in AD pathogenesis. LRP1 regulates inflammatory responses in peripheral tissues by modulating the release of inflammatory cytokines and phagocytosis. However, the roles of LRP1 in brain innate immunity and neuroinflammation remain unclear. METHODS: In this study, we determined whether LRP1 modulates microglial activation by knocking down Lrp1 in mouse primary microglia. LRP1-related functions in microglia were also assessed in the presence of LRP1 antagonist, the receptor-associated protein (RAP). The effects on the production of inflammatory cytokines were measured by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Potential involvement of specific signaling pathways in LRP1-regulated functions including mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) were assessed using specific inhibitors. RESULTS: We found that knocking down of Lrp1 in mouse primary microglia led to the activation of both c-Jun N-terminal kinase (JNK) and NF-κB pathways with corresponding enhanced sensitivity to lipopolysaccharide (LPS) in the production of pro-inflammatory cytokines. Similar effects were observed when microglia were treated with LRP1 antagonist RAP. In addition, treatment with pro-inflammatory stimuli suppressed Lrp1 expression in microglia. Interestingly, NF-κB inhibitor not only suppressed the production of cytokines induced by the knockdown of Lrp1 but also restored the down-regulated expression of Lrp1 by LPS. CONCLUSIONS: Our study uncovers that LRP1 suppresses microglial activation by modulating JNK and NF-κB signaling pathways. Given that dysregulation of LRP1 has been associated with AD pathogenesis, our work reveals a critical regulatory mechanism of microglial activation by LRP1 that could be associated with other AD-related pathways thus further nominating LRP1 as a potential disease-modifying target for the treatment of AD.
[Mh] Termos MeSH primário: MAP Quinase Quinase 4/metabolismo
Microglia/imunologia
NF-kappa B/metabolismo
Receptores de LDL/metabolismo
Transdução de Sinais/fisiologia
Proteínas Supressoras de Tumor/metabolismo
[Mh] Termos MeSH secundário: Peptídeos beta-Amiloides/farmacologia
Animais
Animais Recém-Nascidos
Células Cultivadas
Citocinas/genética
Citocinas/metabolismo
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/farmacologia
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/genética
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/farmacologia
Lipopolissacarídeos/farmacologia
Camundongos
Camundongos Endogâmicos C57BL
Microglia/efeitos dos fármacos
Fragmentos de Peptídeos/farmacologia
RNA Mensageiro/metabolismo
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Receptores de LDL/genética
Transdução de Sinais/efeitos dos fármacos
Transfecção
Proteínas Supressoras de Tumor/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Cytokines); 0 (Enzyme Inhibitors); 0 (LDL-Receptor Related Protein-Associated Protein); 0 (Lipopolysaccharides); 0 (Lrp1 protein, mouse); 0 (NF-kappa B); 0 (Peptide Fragments); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Receptors, LDL); 0 (Tumor Suppressor Proteins); 0 (amyloid beta-protein (1-42)); EC 2.7.12.2 (MAP Kinase Kinase 4)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE


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[PMID]:27402839
[Au] Autor:Prasad JM; Young PA; Strickland DK
[Ad] Endereço:From the Center for Vascular and Inflammatory Disease and the Departments of Surgery and Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
[Ti] Título:High Affinity Binding of the Receptor-associated Protein D1D2 Domains with the Low Density Lipoprotein Receptor-related Protein (LRP1) Involves Bivalent Complex Formation: CRITICAL ROLES OF LYSINES 60 AND 191.
[So] Source:J Biol Chem;291(35):18430-9, 2016 08 26.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that binds and mediates the endocytosis of numerous structurally diverse ligands. Currently, the basis for ligand recognition by LRP1 is not well understood. LRP1 requires a molecular chaperone, termed the receptor-associated protein (RAP), to escort the newly synthesized receptor from the endoplasmic reticulum to the Golgi. RAP is a three-domain protein that contains the following two high affinity binding sites for LRP1: one is located within domains 1 and 2, and one is located in its third domain. Studies on the interaction of the RAP third domain with LRP1 reveal critical contributions by lysine 256 and lysine 270 for this interaction. From these studies, a model for ligand recognition by this class of receptors has been proposed. Here, we employed surface plasmon resonance to investigate the binding of RAP D1D2 to LRP1. Our results reveal that the high affinity of D1D2 for LRP1 results from avidity effects mediated by the simultaneous interactions of lysine 60 in D1 and lysine 191 in D2 with sites on LRP1 to form a bivalent D1D2-LRP1 complex. When lysine 60 and 191 are both mutated to alanine, the binding of D1D2 to LRP1 is ablated. Our data also reveal that D1D2 is able to bind to a second distinct site on LRP1 to form a monovalent complex. The studies confirm the canonical model for ligand recognition by this class of receptors, which is initiated by pairs of lysine residues that dock into acidic pockets on the receptor.
[Mh] Termos MeSH primário: Proteína Associada a Proteínas Relacionadas a Receptor de LDL/química
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Modelos Moleculares
Complexos Multiproteicos/química
[Mh] Termos MeSH secundário: Seres Humanos
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Lisina/química
Lisina/genética
Lisina/metabolismo
Complexos Multiproteicos/genética
Complexos Multiproteicos/metabolismo
Ligação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (LDL-Receptor Related Protein-Associated Protein); 0 (LRP1 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Multiprotein Complexes); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160713
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.744904


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[PMID]:27094046
[Au] Autor:Lisi S; Botta R; Rotondo Dottore G; Leo M; Latrofa F; Vitti P; Marinò M
[Ad] Endereço:Department of Clinical and Experimental Medicine, Endocrinology Unit I, University of Pisa and University Hospital of Pisa, Via Paradisa 2, 56124, Pisa, Italy.
[Ti] Título:Intracellular retention of thyroglobulin in the absence of the low-density lipoprotein receptor-associated protein (RAP) is likely due to premature binding to megalin in the biosynthetic pathway.
[So] Source:J Endocrinol Invest;39(9):1039-44, 2016 Sep.
[Is] ISSN:1720-8386
[Cp] País de publicação:Italy
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The low-density lipoprotein receptor associated protein (RAP) is expressed by thyroid epithelial cells (TEC) in a TSH-dependent manner. In the thyroid RAP functions as a molecular chaperone for the thyroglobulin (Tg) endocytic receptor megalin/LRP2, which is retained intracellularly in RAP KO mice rather than being expressed on the apical membrane of TEC, its usual location. RAP binds also to Tg, which is also retained intracellularly in RAP KO mice, thereby suggesting a role of RAP in Tg secretion. Here we investigated whether Tg intracellular retention in the absence of RAP is due to premature Tg-megalin interactions during the biosynthetic pathway or to a direct action of RAP on Tg secretion. METHODS: We performed immunoprecipitation experiments in thyroid extracts from RAP KO and WT mice. In addition, we investigated Tg secretion in COS-7 cells co-transfected with human RAP (hRAP) and mouse Tg (mTg). RESULTS: An anti-megalin megalin precipitated greater amounts of Tg in thyroid extracts from RAP KO than from WT mice, suggesting increased intracellular interactions between megalin and Tg in the absence of RAP. COS-7 cells transiently transfected with hRAP, mTg or both, expressed the two proteins accordingly. RAP was found almost exclusively in cell extracts, whereas Tg was found both in extracts and media, as expected from the knowledge that RAP is ER-resident and that Tg is secreted. Regardless of whether cells were transfected with mTg alone or were co-transfected with hRAP, similar proportions of the total Tg synthesized were detected in cell extracts and media. CONCLUSIONS: The intracellular retention of Tg in the absence of RAP is likely due to its premature interaction with megalin, whereas RAP does not seem to affect Tg secretion directly.
[Mh] Termos MeSH primário: Vias Biossintéticas
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/fisiologia
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Tireoglobulina/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Western Blotting
Feminino
Seres Humanos
Masculino
Camundongos
Camundongos Knockout
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (LDL-Receptor Related Protein-Associated Protein); 0 (Low Density Lipoprotein Receptor-Related Protein-2); 9010-34-8 (Thyroglobulin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160421
[St] Status:MEDLINE
[do] DOI:10.1007/s40618-016-0464-2


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[PMID]:26679211
[Au] Autor:Vilahur N; Bustamante M; Morales E; Motta V; Fernandez MF; Salas LA; Escaramis G; Ballester F; Murcia M; Tardon A; Riaño I; Santa-Marina L; Ibarluzea J; Arrebola JP; Estivill X; Bollati V; Sunyer J; Olea N
[Ad] Endereço:ISGlobal, Center for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
[Ti] Título:Prenatal exposure to mixtures of xenoestrogens and genome-wide DNA methylation in human placenta.
[So] Source:Epigenomics;8(1):43-54, 2016 Jan.
[Is] ISSN:1750-192X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: In utero exposure to xenostrogens may modify the epigenome. We explored the association of prenatal exposure to mixtures of xenoestrogens and genome-wide placental DNA methylation. MATERIALS & METHODS: Sex-specific associations between methylation changes in placental DNA by doubling the concentration of TEXB-alpha exposure were evaluated by robust multiple linear regression. Two CpG sites were selected for validation and replication in additional male born placentas. RESULTS: No significant associations were found, although the top significant CpGs in boys were located in the LRPAP1, HAGH, PPARGC1B, KCNQ1 and KCNQ1DN genes, previously associated to birth weight, Type 2 diabetes, obesity or steroid hormone signaling. Neither technical validation nor biological replication of the results was found in boys for LRPAP and PPARGC1B. CONCLUSION: Some suggestive genes were differentially methylated in boys in relation to prenatal xenoestrogen exposure, but our initial findings could not be validated or replicated.
[Mh] Termos MeSH primário: Metilação de DNA
Estrogênios/toxicidade
Estudo de Associação Genômica Ampla/métodos
Placenta/efeitos dos fármacos
Efeitos Tardios da Exposição Pré-Natal/genética
[Mh] Termos MeSH secundário: Peso ao Nascer
Proteínas de Transporte/genética
Ilhas de CpG
Epigênese Genética
Feminino
Seres Humanos
Canal de Potássio KCNQ1/genética
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética
Masculino
Gravidez
Fatores Sexuais
Tioléster Hidrolases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Estrogens); 0 (KCNQ1 Potassium Channel); 0 (KCNQ1 protein, human); 0 (LDL-Receptor Related Protein-Associated Protein); 0 (PPARGC1B protein, human); EC 3.1.2.- (Thiolester Hydrolases); EC 3.1.2.6 (hydroxyacylglutathione hydrolase)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151219
[St] Status:MEDLINE
[do] DOI:10.2217/epi.15.91


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[PMID]:26474495
[Au] Autor:Chintala SK
[Ad] Endereço:Laboratory of Ophthalmic Neurobiology, Eye Research Institute of Oakland University, 2200 N. Squirrel Road, 409 DHE, Rochester MI 48309, USA. Electronic address: Chintala@oakland.edu.
[Ti] Título:Tissue and urokinase plasminogen activators instigate the degeneration of retinal ganglion cells in a mouse model of glaucoma.
[So] Source:Exp Eye Res;143:17-27, 2016 Feb.
[Is] ISSN:1096-0007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Elevated intraocular pressure (IOP) promotes the degeneration of retinal ganglion cells (RGCs) during the progression of Primary Open-Angle Glaucoma (POAG). However, the molecular mechanisms underpinning IOP-mediated degeneration of RGCs remain unclear. Therefore, by employing a mouse model of POAG, this study examined whether elevated IOP promotes the degeneration of RGCs by up-regulating tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) in the retina. IOP was elevated in mouse eyes by injecting fluorescent-microbeads into the anterior chamber. Once a week, for eight weeks, IOP in mouse eyes was measured by using Tono-Pen XL. At various time periods after injecting microbeads, proteolytic activity of tPA and uPA in retinal protein extracts was determined by fibrinogen/plasminogen zymography assays. Localization of tPA and uPA, and their receptor LRP-1 (low-density receptor-related protein-1) in the retina was determined by immunohistochemistry. RGCs' degeneration was assessed by immunostaining with antibodies against Brn3a. Injection of microbeads into the anterior chamber led to a progressive elevation in IOP, increased the proteolytic activity of tPA and uPA in the retina, activated plasminogen into plasmin, and promoted a significant degeneration of RGCs. Elevated IOP up-regulated tPA and LRP-1 in RGCs, and uPA in astrocytes. At four weeks after injecting microbeads, RAP (receptor associated protein; 0.5 and 1.0 µM) or tPA-Stop (1.0 and 4.0 µM) was injected into the vitreous humor. Treatment of IOP-elevated eyes with RAP led to a significant decrease in proteolytic activity of both tPA and uPA, and a significant decrease in IOP-mediated degeneration of RGCs. Also, treatment of IOP-elevated eyes with tPA-Stop decreased the proteolytic activity of both tPA and uPA, and, in turn, significantly attenuated IOP-mediated degeneration of RGCs. Results presented in this study provide evidence that elevated IOP promotes the degeneration of RGCs by up-regulating the levels of proteolytically active tPA and uPA.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Glaucoma de Ângulo Aberto/metabolismo
Degeneração Retiniana/metabolismo
Células Ganglionares da Retina/metabolismo
Ativador de Plasminogênio Tecidual/metabolismo
Ativador de Plasminogênio Tipo Uroquinase/metabolismo
[Mh] Termos MeSH secundário: Amidinas/farmacologia
Animais
Compostos de Benzilideno/farmacologia
Western Blotting
Inibidores do Fator Xa/farmacologia
Fibrinolisina/metabolismo
Técnica Indireta de Fluorescência para Anticorpo
Glaucoma de Ângulo Aberto/patologia
Pressão Intraocular/fisiologia
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/farmacologia
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Microesferas
Plasminogênio/metabolismo
Degeneração Retiniana/patologia
Células Ganglionares da Retina/patologia
Tonometria Ocular
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amidines); 0 (Benzylidene Compounds); 0 (Factor Xa Inhibitors); 0 (LDL-Receptor Related Protein-Associated Protein); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (ZK 805412); 9001-91-6 (Plasminogen); EC 3.4.21.68 (Tissue Plasminogen Activator); EC 3.4.21.7 (Fibrinolysin); EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151018
[St] Status:MEDLINE


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[PMID]:26271838
[Au] Autor:Khan AO; Aldahmesh MA; Alkuraya FS
[Ad] Endereço:Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Electronic address: arif.khan@mssm.edu.
[Ti] Título:Clinical Characterization of LRPAP1-Related Pediatric High Myopia.
[So] Source:Ophthalmology;123(2):434-5, 2016 Feb.
[Is] ISSN:1549-4713
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Distrofias Hereditárias da Córnea/diagnóstico
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética
Miopia Degenerativa/diagnóstico
Miopia Degenerativa/genética
Doenças do Nervo Óptico/diagnóstico
[Mh] Termos MeSH secundário: Adolescente
Criança
Pré-Escolar
Distrofias Hereditárias da Córnea/genética
Análise Mutacional de DNA
Feminino
Seres Humanos
Masculino
Mutação
Doenças do Nervo Óptico/genética
Acuidade Visual
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (LDL-Receptor Related Protein-Associated Protein)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160124
[Lr] Data última revisão:
160124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150815
[St] Status:MEDLINE


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[PMID]:26084411
[Au] Autor:Li P; Wu J; Zhao L; Feng XW
[Ad] Endereço:Department of Respiratory Medicine, Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, China.
[Ti] Título:Effects and relationship of intermittent hypoxia on serum lipid levels, hepatic low-density lipoprotein receptor-related protein 1, and hypoxia-inducible factor 1α.
[So] Source:Sleep Breath;20(1):167-73, 2016 Mar.
[Is] ISSN:1522-1709
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: This study investigated the influence of intermittent hypoxia on serum lipid level, hepatic low-density lipoprotein receptor-related protein (LRP)1, and hepatic hypoxia-inducible factor (HIF)-1α and the underlying mechanisms of action. METHODS: Male Sprague Dawley rats were subjected to different levels of hypoxia. After 1-4 weeks hypoxemia, routine blood tests were performed and the levels of LRP1 and HIF-1α in liver were examined. Intermittent hypoxia (IH) was induced in HepG2 cells with or without HIF-1α inhibitor YC-1 pretreatment, and the levels of LRP1 and HIF-1α in cells were examined. RESULTS: IH caused elevated serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein in rats. IH caused elevated hepatic levels of LRP1 and HIF-1α. After pretreatment with YC-1, HIF-1α protein expression decreased but mRNA expression did not change in HepG2 cells. CONCLUSIONS: IH caused dyslipidemia and elevated LRP1 and HIF-1α. Elevated LRP1 expression was caused by HIF-1α.
[Mh] Termos MeSH primário: Hipóxia Celular/fisiologia
Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/sangue
Lipídeos/sangue
Fígado/fisiopatologia
Apneia Obstrutiva do Sono/sangue
[Mh] Termos MeSH secundário: Animais
Células Hep G2
Seres Humanos
Masculino
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hif1a protein, rat); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (LDL-Receptor Related Protein-Associated Protein); 0 (Lipids)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150619
[St] Status:MEDLINE
[do] DOI:10.1007/s11325-015-1200-4


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[PMID]:26013822
[Au] Autor:Prasad JM; Migliorini M; Galisteo R; Strickland DK
[Ad] Endereço:From the Center for Vascular and Inflammatory Disease and the Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201.
[Ti] Título:Generation of a Potent Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Antagonist by Engineering a Stable Form of the Receptor-associated Protein (RAP) D3 Domain.
[So] Source:J Biol Chem;290(28):17262-8, 2015 Jul 10.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The low density lipoprotein receptor-related protein 1 (LRP1) is a member of the low density lipoprotein receptor family and plays important roles in a number of physiological and pathological processes. Expression of LRP1 requires the receptor-associated protein (RAP), a molecular chaperone that binds LRP1 and other low density lipoprotein receptor family members in the endoplasmic reticulum and traffics with them to the Golgi where the acidic environment causes its dissociation. Exogenously added RAP is a potent LRP1 antagonist and binds to LRP1 on the cell surface, preventing ligands from binding. Following endocytosis, RAP dissociates in the acidic endosome, allowing LRP1 to recycle back to the cell surface. The acid-induced dissociation of RAP is mediated by its D3 domain, a relatively unstable three-helical bundle that denatures at pH <6.2 due to protonation of key histidine residues on helices 2 and 3. To develop an LRP1 inhibitor that does not dissociate at low pH, we introduced a disulfide bond between the second and third helices in the RAP D3 domain. By combining this disulfide bond with elimination of key histidine residues, we generated a stable RAP molecule that is resistant to both pH- and heat-induced denaturation. This molecule bound to LRP1 with high affinity at both neutral and acidic pH and proved to be a potent inhibitor of LRP1 function both in vitro and in vivo, suggesting that our stable RAP molecule may be useful in multiple pathological settings where LRP1 blockade has been shown to be effective.
[Mh] Termos MeSH primário: Proteína Associada a Proteínas Relacionadas a Receptor de LDL/química
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/farmacologia
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores
Receptores de LDL/antagonistas & inibidores
Proteínas Supressoras de Tumor/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Seres Humanos
Concentração de Íons de Hidrogênio
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética
Camundongos
Camundongos Endogâmicos C57BL
Modelos Moleculares
Mutagênese Sítio-Dirigida
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/farmacologia
Ligação Proteica
Desnaturação Proteica
Engenharia de Proteínas
Estabilidade Proteica
Estrutura Secundária de Proteína
Estrutura Terciária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (LDL-Receptor Related Protein-Associated Protein); 0 (LRP1 protein, human); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Lrp1 protein, mouse); 0 (Peptide Fragments); 0 (Receptors, LDL); 0 (Tumor Suppressor Proteins)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150528
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M115.660084


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[PMID]:25728577
[Au] Autor:Bloem E; Ebberink EH; van den Biggelaar M; van der Zwaan C; Mertens K; Meijer AB
[Ad] Endereço:*Department of Plasma Proteins, Sanquin Research, Amsterdam 1066CX, The Netherlands.
[Ti] Título:A novel chemical footprinting approach identifies critical lysine residues involved in the binding of receptor-associated protein to cluster II of LDL receptor-related protein.
[So] Source:Biochem J;468(1):65-72, 2015 May 15.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tandem mass tags (TMTs) were utilized in a novel chemical footprinting approach to identify lysine residues that mediate the interaction of receptor-associated protein (RAP) with cluster II of LDL (low-density lipoprotein) receptor (LDLR)-related protein (LRP). The isolated RAP D3 domain was modified with TMT-126 and the D3 domain-cluster II complex with TMT-127. Nano-LC-MS analysis revealed reduced modification with TMT-127 of peptides including Lys(256), Lys(270) and Lys(305)-Lys(306) suggesting that these residues contribute to cluster II binding. This agrees with previous findings that Lys(256) and Lys(270) are critical for binding cluster II sub-domains [Fisher, Beglova and Blacklow (2006) Mol. Cell 22, 277-283]. Cluster II-binding studies utilizing D3 domain variants K(256)A, K(305)A and K(306)A now showed that Lys(306) contributes to cluster II binding as well. For full-length RAP, we observed that peptides including Lys(60), Lys(191), Lys(256), Lys(270) and Lys(305)-Lys(306) exhibited reduced modification with TMT in the RAP-cluster II complex. Notably, Lys(60) has previously been implicated to mediate D1 domain interaction with cluster II. Our results suggest that also Lys(191) of the D2 domain contributes to cluster II binding. Binding studies employing the RAP variants K(191)A, K(256)A, K(305)A and K(306)A, however, revealed a modest reduction in cluster II binding for the K(256)A variant only. This suggests that the other lysine residues can compensate for the absence of a single lysine residue for effective complex assembly. Collectively, novel insight has been obtained into the contribution of lysine residues of RAP to cluster II binding. In addition, we propose that TMTs can be utilized to identify lysine residues critical for protein complex formation.
[Mh] Termos MeSH primário: Proteína Associada a Proteínas Relacionadas a Receptor de LDL/química
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos
Animais
Sítios de Ligação/genética
Seres Humanos
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/genética
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Lisina/química
Modelos Moleculares
Mutagênese Sítio-Dirigida
Ligação Proteica
Pegadas de Proteínas/métodos
Domínios e Motivos de Interação entre Proteínas
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (LDL-Receptor Related Protein-Associated Protein); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Recombinant Proteins); K3Z4F929H6 (Lysine)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:150505
[Lr] Data última revisão:
150505
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150303
[St] Status:MEDLINE
[do] DOI:10.1042/BJ20140977



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