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https://www.readbyqxmd.com/read/28516428/cerebrovascular-angiogenic-reprogramming-upon-lrp1-repression-impact-on-sphingosine-1-phosphate-mediated-signaling-in-brain-endothelial-cell-chemotactism
#1
Amélie Vézina, Cyndia Charfi, Alain Zgheib, Borhane Annabi
Switches in sphingolipid metabolism have recently been associated with oncogenic transformation, and a role for the low-density lipoprotein receptor-related protein 1 (LRP1) in sphingosine-1-phosphate (S1P) proangiogenic signaling inferred. S1P signaling crosstalk with LRP1 in brain microvascular endothelial cells (HBMEC) is however unclear. Transient in vitro siLRP1 gene silencing was compared to stable shLRP1 knockdown. We observed decreased expression of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor for which multiple binding sites are found within the promoter sequences of all five S1P receptor members, upon stable but not transient LRP1 repression...
May 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28496400/lrp1-modulates-app-intraneuronal-transport-and-processing-in-its-monomeric-and-dimeric-state
#2
Uta-Mareike Herr, Paul Strecker, Steffen E Storck, Carolin Thomas, Verena Rabiej, Anne Junker, Sandra Schilling, Nadine Schmidt, C Marie Dowds, Simone Eggert, Claus U Pietrzik, Stefan Kins
The low-density lipoprotein receptor-related protein 1, LRP1, interacts with APP and affects its processing. This is assumed to be mostly caused by the impact of LRP1 on APP endocytosis. More recently, also an interaction of APP and LRP1 early in the secretory pathway was reported whereat retention of LRP1 in the ER leads to decreased APP cell surface levels and in turn, to reduced Aβ secretion. Here, we extended the biochemical and immunocytochemical analyses by showing via live cell imaging analyses in primary neurons that LRP1 and APP are transported only partly in common (one third) but to a higher degree in distinct fast axonal transport vesicles...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28495363/app-aplp2-and-lrp1-interact-with-pcsk9-but-are-not-required-for-pcsk9-mediated-degradation-of-the-ldlr-in-vivo
#3
Ting Fu, YangYang Guan, Junjie Xu, Yan Wang
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that post-transcriptionally regulates the levels of hepatic low-density lipoprotein receptors (LDLRs). PCSK9 binds to the extracellular domain of the LDLR, and the PCSK9-LDLR complex is internalized through canonical clathrin-dependent endocytosis and then delivered to lysosomes for degradation. The mechanism by which PCSK9 blocks recycling of the LDLR has not been fully defined. Previous reports showed that amyloid precursor-like protein 2 (APLP2) interacts with PCSK9, but its role in PCSK9-mediated LDLR degradation remains controversial...
May 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28487135/estrogen-enhanced-apical-and-basolateral-secretion-of-apolipoprotein-b-100-by-polarized-trophoblast-derived-bewo-cells
#4
Miriam Kamper, Florian Mittermayer, Rosalinda Cabuk, Katharina Gelles, Isabella Ellinger, Marcela Hermann
Cholesterol is an important nutrient for fetal development and transplacental transport occurs at all stages of human pregnancy. Furthermore, cholesterol is required for membrane building as well as steroid hormone synthesis. Therefore, all placental cell types require cholesterol for proper function. In human term placenta, the syncytiotrophoblast (STB) faces the maternal circulation. Uptake of maternal-derived cholesterol at the apical membrane of the STB is well understood, but the route by which cholesterol exits at the basal side for subsequent transfer across the fetal endothelial cells (FEC) or to other placental cell types remains not well characterized...
May 6, 2017: Biochimie
https://www.readbyqxmd.com/read/28482944/increased-birth-weight-is-associated-with-altered-gene-expression-in-neonatal-foreskin
#5
L J Reynolds, R I Pollack, R J Charnigo, C S Rashid, A J Stromberg, S Shen, J M O'Brien, K J Pearson
Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n=7) v...
May 9, 2017: Journal of Developmental Origins of Health and Disease
https://www.readbyqxmd.com/read/28478826/novel-aspects-of-defensins-involvement-in-virus-induced-autoimmunity-in-the-central-nervous-system
#6
Evangelos I Kazakos, Jannis Kountouras, Stergios A Polyzos, Georgia Deretzi
Recent research on re-circulation of interstitial fluid from the brain parenchyma to the periphery and its inferred importance in immune surveillance dysregulation are changing our conceptualization of the pathophysiology of virus-induced autoimmunity. In this context, it is necessary to reassess the immunomodulatory properties of human defensins that are variably expressed by cerebral microglia, astrocytes and choroid plexus epithelial cells and exhibit complex and often confounding roles in neuroinflammatory processes...
May 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/28473440/deficiency-of-lrp1-in-mature-adipocytes-promotes-diet-induced-inflammation-and-atherosclerosis
#7
Eddy S Konaniah, David G Kuhel, Joshua E Basford, Neal L Weintraub, David Y Hui
OBJECTIVE: Mice with adipocyte-specific inactivation of low-density lipoprotein receptor-related protein-1 (LRP1) are resistant to diet-induced obesity and hyperglycemia because of compensatory thermogenic response by muscle. However, the physiological function of LRP1 in mature adipocytes and its role in cardiovascular disease modulation are unknown. This study compared perivascular adipose tissues (PVAT) from wild-type (adLrp1(+/+) ) and adipocyte-specific LRP1 knockout (adLrp1(-/-)) mice in modulation of atherosclerosis progression...
May 4, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28431990/a-common-polymorphism-decreases-lrp1-mrna-stability-and-is-associated-with-increased-plasma-factor-viii-levels
#8
Jiann-Der Lee, Kuang-Ming Hsiao, Pey-Jium Chang, Chih-Cheng Chen, Ya-Wen Kuo, Yen-Chu Huang, Huan-Lin Hsu, Ya-Hui Lin, Chih-Ying Wu, Ying-Chih Huang, Meng Lee, Chia-Yu Hsu, Yi-Ting Pan, Chih-Yu Kuo, Chun-Hsien Lin
The low-density lipoprotein receptor-related protein 1 (LRP1) gene is associated with increased levels of plasma factor VIII (FVIII). We aimed to explore eight functional genetic LRP1 variants for their potential roles in regulating FVIII levels and acute ischemic stroke (AIS). This genetic association study enrolled 192 patients with AIS and 134 controls. There were no significant differences in the genetic frequency of the eight functional single-nucleotide polymorphisms (SNPs) between the control and AIS groups...
April 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28393867/endothelial-lrp1-regulates-metabolic-responses-by-acting-as-a-co-activator-of-ppar%C3%AE
#9
Hua Mao, Pamela Lockyer, Luge Li, Christie M Ballantyne, Cam Patterson, Liang Xie, Xinchun Pi
Low-density lipoprotein receptor-related protein 1 (LRP1) regulates lipid and glucose metabolism in liver and adipose tissue. It is also involved in central nervous system regulation of food intake and leptin signalling. Here we demonstrate that endothelial Lrp1 regulates systemic energy homeostasis. Mice with endothelial-specific Lrp1 deletion display improved glucose sensitivity and lipid profiles combined with increased oxygen consumption during high-fat-diet-induced obesity. We show that the intracellular domain of Lrp1 interacts with the nuclear receptor Pparγ, a central regulator of lipid and glucose metabolism, acting as its transcriptional co-activator in endothelial cells...
April 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28381441/role-of-lrp1-in-the-pathogenesis-of-alzheimer-s-disease-evidence-from-clinical-and-preclinical-studies
#10
Mitsuru Shinohara, Masaya Tachibana, Takahisa Kanekiyo, Guojun Bu
Among the low-density lipoprotein receptor (LDLR) family members, the roles of LDLR-related protein 1 (LRP1 or LRP) in the pathogenesis of Alzheimer's disease (AD), especially late-onset AD, have been the most studied by genetic, neuropathological and biomarker analyses (clinical studies) or cellular and animal model systems (preclinical studies) over the last 25 years. Although there are some conflicting reports, accumulating evidence from preclinical studies indicates that LRP1 not only regulates the metabolism of amyloid-β peptides (Aβ) in the brain and periphery, but also maintains brain homeostasis, impairment of which likely contributes to AD development in Aβ-independent manners...
April 4, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28378397/relationship-among-lrp1-expression-pyk2-phosphorylation-and-mmp-9-activation-in-left-ventricular-remodelling-after-myocardial-infarction
#11
Elena Revuelta-López, Carol Soler-Botija, Laura Nasarre, Aleyda Benitez-Amaro, David de Gonzalo-Calvo, Antoni Bayes-Genis, Vicenta Llorente-Cortés
Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metalloproteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the activation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore the potential association between the low-density lipoprotein receptor-related protein 1 (LRP1) and MMP-9 and MMP-2 spatiotemporal expression after MI...
April 4, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28356732/angiopep-2-conjugated-poly-ethylene-glycol-co-poly-%C3%AE%C2%B5-caprolactone-polymersomes-for-dual-targeting-drug-delivery-to-glioma-in-rats
#12
Fei Lu, Zhiyong Pang, Jingjing Zhao, Kai Jin, Haichun Li, Qiang Pang, Long Zhang, Zhiqing Pang
The blood-brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX) was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1), which is overexpressed in both blood-brain barrier and glioma cells. The polymersomes (PS) were prepared using a thin-film hydration method...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28306378/development-of-a-monoclonal-anti-adamts-5-antibody-that-specifically-blocks-the-interaction-with-lrp1
#13
Salvatore Santamaria, Oleg Fedorov, John McCafferty, Gillian Murphy, Jayesh Dudhia, Hideaki Nagase, Kazuhiro Yamamoto
The potent aggrecanase ADAMTS-5 is constitutively secreted by chondrocytes, but it is rapidly endocytosed in normal cartilage via the cell surface endocytic receptor LRP1. Therefore it is difficult to detect the total ADAMTS-5 activity produced. In this study, we isolated a monoclonal anti-ADAMTS-5 antibody 1B7 that blocks LRP1-mediated internalization without affecting the aggrecanolytic activity. Addition of 1B7 to cultured human chondrocytes revealed the full aggrecanolytic activity of ADAMTS-5 generated by the cells...
May 2017: MAbs
https://www.readbyqxmd.com/read/28301372/news-on-the-molecular-regulation-and-function-of-hepatic-low-density-lipoprotein-receptor-and-ldlr-related-protein-1
#14
Bart van de Sluis, Melinde Wijers, Joachim Herz
PURPOSE OF REVIEW: Clearing of atherogenic lipoprotein particles by the liver requires hepatic low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1). This review highlights recent studies that have expanded our understanding of the molecular regulation and metabolic functions of LDLR and LRP1 in the liver. RECENT FINDINGS: Various proteins orchestrate the intracellular trafficking of LDLR and LRP1. After internalization, the receptors are redirected via recycling endosomes to the cell surface...
June 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28275161/astrocytic-lrp1-mediates-brain-a%C3%AE-clearance-and-impacts-amyloid-deposition
#15
Chia-Chen Liu, Jin Hu, Na Zhao, Jian Wang, Na Wang, John R Cirrito, Takahisa Kanekiyo, David M Holtzman, Guojun Bu
Accumulation and deposition of amyloid-β (Aβ) in the brain represent an early and perhaps necessary step in the pathogenesis of Alzheimer's disease (AD). Aβ accumulation leads to the formation of Aβ aggregates, which may directly and indirectly lead to eventual neurodegeneration. While Aβ production is accelerated in many familial forms of early-onset AD, increasing evidence indicates that impaired clearance of Aβ is more evident in late-onset AD. To uncover the mechanisms underlying impaired Aβ clearance in AD, we examined the role of low-density lipoprotein receptor-related protein 1 (LRP1) in astrocytes...
April 12, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28263310/deficiency-of-the-hepatokine-selenoprotein-p-increases-responsiveness-to-exercise-in-mice-through-upregulation-of-reactive-oxygen-species-and-amp-activated-protein-kinase-in-muscle
#16
Hirofumi Misu, Hiroaki Takayama, Yoshiro Saito, Yuichiro Mita, Akihiro Kikuchi, Kiyo-Aki Ishii, Keita Chikamoto, Takehiro Kanamori, Natsumi Tajima, Fei Lan, Yumie Takeshita, Masao Honda, Mutsumi Tanaka, Seiji Kato, Naoto Matsuyama, Yuya Yoshioka, Kaito Iwayama, Kumpei Tokuyama, Nobuhiko Akazawa, Seiji Maeda, Kazuhiro Takekoshi, Seiichi Matsugo, Noriko Noguchi, Shuichi Kaneko, Toshinari Takamura
Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle...
April 2017: Nature Medicine
https://www.readbyqxmd.com/read/28256585/lrp1-influences-trafficking-of-n-type-calcium-channels-via-interaction-with-the-auxiliary-%C3%AE-2%C3%AE-1-subunit
#17
Ivan Kadurin, Simon W Rothwell, Beatrice Lana, Manuela Nieto-Rostro, Annette C Dolphin
Voltage-gated Ca(2+) (CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28228716/intranasal-bmp9-ameliorates-alzheimer-disease-like-pathology-and-cognitive-deficits-in-app-ps1-transgenic-mice
#18
Zigao Wang, Lu Xiong, Wenbin Wan, Lijie Duan, Xiaojing Bai, Hengbing Zu
Alzheimer's disease (AD) is the most common type of dementia and has no effective therapies. Previous studies showed that bone morphogenetic protein 9 (BMP9), an important factor in the differentiation and phenotype maintenance of cholinergic neurons, ameliorated the cholinergic defects resulting from amyloid deposition. These findings suggest that BMP9 has potential as a therapeutic agent for AD. However, the effects of BMP9 on cognitive function in AD and its underlying mechanisms remain elusive. In the present study, BMP9 was delivered intranasally to 7-month-old APP/PS1 mice for 4 weeks...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28209224/systematic-evaluation-of-pleiotropy-identifies-6-further-loci-associated-with%C3%A2-coronary-artery%C3%A2-disease
#19
Thomas R Webb, Jeanette Erdmann, Kathleen E Stirrups, Nathan O Stitziel, Nicholas G D Masca, Henning Jansen, Stavroula Kanoni, Christopher P Nelson, Paola G Ferrario, Inke R König, John D Eicher, Andrew D Johnson, Stephen E Hamby, Christer Betsholtz, Arno Ruusalepp, Oscar Franzén, Eric E Schadt, Johan L M Björkegren, Peter E Weeke, Paul L Auer, Ursula M Schick, Yingchang Lu, He Zhang, Marie-Pierre Dube, Anuj Goel, Martin Farrall, Gina M Peloso, Hong-Hee Won, Ron Do, Erik van Iperen, Jochen Kruppa, Anubha Mahajan, Robert A Scott, Christina Willenborg, Peter S Braund, Julian C van Capelleveen, Alex S F Doney, Louise A Donnelly, Rosanna Asselta, Pier A Merlini, Stefano Duga, Nicola Marziliano, Josh C Denny, Christian Shaffer, Nour Eddine El-Mokhtari, Andre Franke, Stefanie Heilmann, Christian Hengstenberg, Per Hoffmann, Oddgeir L Holmen, Kristian Hveem, Jan-Håkan Jansson, Karl-Heinz Jöckel, Thorsten Kessler, Jennifer Kriebel, Karl L Laugwitz, Eirini Marouli, Nicola Martinelli, Mark I McCarthy, Natalie R Van Zuydam, Christa Meisinger, Tõnu Esko, Evelin Mihailov, Stefan A Escher, Maris Alver, Susanne Moebus, Andrew D Morris, Jarma Virtamo, Majid Nikpay, Oliviero Olivieri, Sylvie Provost, Alaa AlQarawi, Neil R Robertson, Karen O Akinsansya, Dermot F Reilly, Thomas F Vogt, Wu Yin, Folkert W Asselbergs, Charles Kooperberg, Rebecca D Jackson, Eli Stahl, Martina Müller-Nurasyid, Konstantin Strauch, Tibor V Varga, Melanie Waldenberger, Lingyao Zeng, Rajiv Chowdhury, Veikko Salomaa, Ian Ford, J Wouter Jukema, Philippe Amouyel, Jukka Kontto, Børge G Nordestgaard, Jean Ferrières, Danish Saleheen, Naveed Sattar, Praveen Surendran, Aline Wagner, Robin Young, Joanna M M Howson, Adam S Butterworth, John Danesh, Diego Ardissino, Erwin P Bottinger, Raimund Erbel, Paul W Franks, Domenico Girelli, Alistair S Hall, G Kees Hovingh, Adnan Kastrati, Wolfgang Lieb, Thomas Meitinger, William E Kraus, Svati H Shah, Ruth McPherson, Marju Orho-Melander, Olle Melander, Andres Metspalu, Colin N A Palmer, Annette Peters, Daniel J Rader, Muredach P Reilly, Ruth J F Loos, Alex P Reiner, Dan M Roden, Jean-Claude Tardif, John R Thompson, Nicholas J Wareham, Hugh Watkins, Cristen J Willer, Nilesh J Samani, Heribert Schunkert, Panos Deloukas, Sekar Kathiresan
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011...
February 21, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28059785/amylin-enhances-amyloid-%C3%AE-peptide-brain-to-blood-efflux-across-the-blood-brain-barrier
#20
Loqman A Mohamed, Haihao Zhu, Youssef M Mousa, Erming Wang, Wei Qiao Qiu, Amal Kaddoumi
Findings from Alzheimer's disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3...
2017: Journal of Alzheimer's Disease: JAD
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