scholarly journals LRP1 mediates the IGF-1-induced GLUT1 expression on the cell surface and glucose uptake in Müller glial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Virginia Actis Dato ◽  
María Cecilia Sánchez ◽  
Gustavo Alberto Chiabrando
Keyword(s):  
Glucose Uptake ◽  
Glial Cells ◽  
Intracellular Signaling ◽  
Glucose Transporter ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Dependent Manner ◽  
Müller Glial Cells ◽  
Glut1 Expression ◽  
Signaling Activation

AbstractInsulin-like Growth Factor-1 (IGF-1) is involved in the normal development and survival of retinal cells. Low-density lipoprotein Receptor-related Protein-1 (LRP1) plays a key role on the regulation of several membrane proteins, such as the IGF-1 receptor (IGF-1R). In brain astrocytes, LRP1 interact with IGF-1R and the glucose transporter type 1 (GLUT1), regulating the glucose uptake in these cells. Although GLUT1 is expressed in retinal Müller Glial Cells (MGCs), its regulation is not clear yet. Here, we investigated whether IGF-1 modulates GLUT1 traffic to plasma membrane (PM) and glucose uptake, as well as the involvement of LRP1 in this process in the human Müller glial-derived cell line (MIO-M1). We found that IGF-1 produced GLUT1 translocation to the PM, in a time-dependent manner involving the intracellular signaling activation of MAPK/ERK and PI3K/Akt pathways, and generated a significant glucose uptake. Moreover, we found a molecular association between LRP1 and GLUT1, which was significantly reduced by IGF-1. Finally, cells treated with specific siRNA for LRP1 showed an impaired GLUT1 expression on PM and decreased glucose uptake induced by IGF-1. We conclude that IGF-1 regulates glucose homeostasis in MGCs involving the expression of LRP1.

Insulin-induced exocytosis regulates the cell surface level of low-density lipoprotein-related protein-1 in Müller Glial cells

2018 ◽  
Vol 475 (9) ◽  
pp. 1669-1685 ◽  
Author(s):  
Virginia Actis Dato ◽  
Rubén A. Grosso ◽  
María C. Sánchez ◽  
Claudio M. Fader ◽  
Gustavo A. Chiabrando
Keyword(s):  
Cell Surface ◽  
Cell Line ◽  
Glial Cells ◽  
Intracellular Signaling ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Rab Gtpases ◽  
Related Protein ◽  
Müller Glial Cells

Low-density lipoprotein (LDL) receptor-related protein-1 (LRP1) is expressed in retinal Müller glial cells (MGCs) and regulates intracellular translocation to the plasma membrane (PM) of the membrane proteins involved in cellular motility and activity. Different functions of MGCs may be influenced by insulin, including the removal of extracellular glutamate in the retina. In the present work, we investigated whether insulin promotes LRP1 translocation to the PM in the Müller glial-derived cell line MIO-M1 (human retinal Müller glial cell-derived cell line). We demonstrated that LRP1 is stored in small vesicles containing an approximate size of 100 nm (mean diameter range of 100–120 nm), which were positive for sortilin and VAMP2, and also incorporated GLUT4 when it was transiently transfected. Next, we observed that LRP1 translocation to the PM was promoted by insulin-regulated exocytosis through intracellular activation of the IR/PI3K/Akt axis and Rab-GTPase proteins such as Rab8A and Rab10. In addition, these Rab-GTPases regulated both the constitutive and insulin-induced LRP1 translocation to the PM. Finally, we found that dominant-negative Rab8A and Rab10 mutants impaired insulin-induced intracellular signaling of the IR/PI3K/Akt axis, suggesting that these GTPase proteins as well as the LRP1 level at the cell surface are involved in insulin-induced IR activation.

scholarly journals LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 182
Author(s):  
Virginia Actis Dato ◽  
Aleyda Benitez-Amaro ◽  
David de Gonzalo-Calvo ◽  
Maximiliano Vazquez ◽  
Gustavo Bonacci ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Intracellular Signaling ◽  
Glucose Transporter ◽  
Low Density Lipoprotein ◽  
Insulin Response ◽  
Density Lipoprotein ◽  
Ldl Particles ◽  
Density Lipoprotein Receptor ◽  
Signaling Activation

The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosis.

scholarly journals Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for apolipoprotein A4 (APOA4) in adipose tissue

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jie Qu ◽  
Sarah Fourman ◽  
Maureen Fitzgerald ◽  
Min Liu ◽  
Supna Nair ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Receptor ◽  
Dependent Manner ◽  
Related Protein ◽  
Density Lipoprotein Receptor ◽  
Lipoprotein Receptor Related Protein

AbstractApolipoprotein A4 (APOA4) is one of the most abundant and versatile apolipoproteins facilitating lipid transport and metabolism. APOA4 is synthesized in the small intestine, packaged onto chylomicrons, secreted into intestinal lymph and transported via circulation to several tissues, including adipose. Since its discovery nearly 4 decades ago, to date, only platelet integrin αIIbβ3 has been identified as APOA4 receptor in the plasma. Using co-immunoprecipitation coupled with mass spectrometry, we probed the APOA4 interactome in mouse gonadal fat tissue, where ApoA4 gene is not transcribed but APOA4 protein is abundant. We demonstrate that lipoprotein receptor-related protein 1 (LRP1) is the cognate receptor for APOA4 in adipose tissue. LRP1 colocalized with APOA4 in adipocytes; it interacted with APOA4 under fasting condition and their interaction was enhanced during lipid feeding concomitant with increased APOA4 levels in plasma. In 3T3-L1 mature adipocytes, APOA4 promoted glucose uptake both in absence and presence of insulin in a dose-dependent manner. Knockdown of LRP1 abrogated APOA4-induced glucose uptake as well as activation of phosphatidylinositol 3 kinase (PI3K)-mediated protein kinase B (AKT). Taken together, we identified LRP1 as a novel receptor for APOA4 in promoting glucose uptake. Considering both APOA4 and LRP1 are multifunctional players in lipid and glucose metabolism, our finding opens up a door to better understand the molecular mechanisms along APOA4-LRP1 axis, whose dysregulation leads to obesity, cardiovascular disease, and diabetes.

scholarly journals Activated α2-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal Müller Glial Cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Javier R. Jaldín-Fincati ◽  
Virginia Actis Dato ◽  
Nicolás M. Díaz ◽  
María C. Sánchez ◽  
Pablo F. Barcelona ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Glial Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Matrix Remodeling ◽  
Müller Glial Cells ◽  
Early Endosomes ◽  
Proliferative Retinopathies ◽  
Exocytic Pathway

Abstract Activated α2-macroglobulin (α2M*) and its receptor, low-density lipoprotein receptor-related protein 1 (LRP1), have been linked to proliferative retinal diseases. In Müller glial cells (MGCs), the α2M*/LRP1 interaction induces cell signaling, cell migration, and extracellular matrix remodeling, processes closely associated with proliferative disorders. However, the mechanism whereby α2M* and LRP1 participate in the aforementioned pathologies remains incompletely elucidated. Here, we investigate whether α2M* regulates both the intracellular distribution and sorting of LRP1 to the plasma membrane (PM) and how this regulation is involved in the cell migration of MGCs. Using a human Müller glial-derived cell line, MIO-M1, we demonstrate that the α2M*/LRP1 complex is internalized and rapidly reaches early endosomes. Afterward, α2M* is routed to degradative compartments, while LRP1 is accumulated at the PM through a Rab10-dependent exocytic pathway regulated by PI3K/Akt. Interestingly, Rab10 knockdown reduces both LRP1 accumulation at the PM and cell migration of MIO-M1 cells induced by α2M*. Given the importance of MGCs in the maintenance of retinal homeostasis, unravelling this molecular mechanism can potentially provide new therapeutic targets for the treatment of proliferative retinopathies.

scholarly journals Activated Alpha-2 Macroglobulin Improves Insulin Response via LRP1 in Lipid-Loaded HL-1 Cardiomyocytes

2021 ◽  
Vol 22 (13) ◽  
pp. 6915
Author(s):  
Virginia Actis Dato ◽  
Gustavo Alberto Chiabrando
Keyword(s):  
Glucose Uptake ◽  
Glucose Transporter ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Insulin Response ◽  
Density Lipoprotein ◽  
Low Density ◽  
Cardiac Damage ◽  
Therapeutic Implications ◽  
Glut4 Expression

Activated alpha-2 Macroglobulin (α2M*) is specifically recognized by the cluster I/II of LRP1 (Low-density lipoprotein Receptor-related Protein-1). LRP1 is a scaffold protein for insulin receptor involved in the insulin-induced glucose transporter type 4 (GLUT4) translocation to plasma membrane and glucose uptake in different types of cells. Moreover, the cluster II of LRP1 plays a critical role in the internalization of atherogenic lipoproteins, such as aggregated Low-density Lipoproteins (aggLDL), promoting intracellular cholesteryl ester (CE) accumulation mainly in arterial intima and myocardium. The aggLDL uptake by LRP1 impairs GLUT4 traffic and the insulin response in cardiomyocytes. However, the link between CE accumulation, insulin action, and cardiac dysfunction are largely unknown. Here, we found that α2M* increased GLUT4 expression on cell surface by Rab4, Rab8A, and Rab10-mediated recycling through PI3K/Akt and MAPK/ERK signaling activation. Moreover, α2M* enhanced the insulin response increasing insulin-induced glucose uptake rate in the myocardium under normal conditions. On the other hand, α2M* blocked the intracellular CE accumulation, improved the insulin response and reduced cardiac damage in HL-1 cardiomyocytes exposed to aggLDL. In conclusion, α2M* by its agonist action on LRP1, counteracts the deleterious effects of aggLDL in cardiomyocytes, which may have therapeutic implications in cardiovascular diseases associated with hypercholesterolemia.

scholarly journals LncRNA HOTAIR regulates glucose transporter Glut1 expression and glucose uptake in macrophages during inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Monira Obaid ◽  
S. M. Nashir Udden ◽  
Prasanna Alluri ◽  
Subhrangsu S. Mandal
Keyword(s):  
Immune Response ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Immune Cells ◽  
Glucose Transporter ◽  
Energy Needs ◽  
Glut1 Expression ◽  
Lncrna Hotair ◽  
Upstream Regulators ◽  
Glucose Transporter Glut1

AbstractInflammation plays central roles in the immune response. Inflammatory response normally requires higher energy and therefore is associated with glucose metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF-kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in the regulation of glucose metabolism in immune cells during inflammation. Our results demonstrate that LPS-induced inflammation induces the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake in macrophages. LPS-induced Glut1 expression is regulated via NF-kB activation. Importantly, siRNA-mediated knockdown of HOTAIR suppressed the LPS-induced expression of Glut1 suggesting key roles of HOTAIR in LPS-induced Glut1 expression in macrophage. HOTAIR induces NF-kB activation, which in turn increases Glut1 expression in response to LPS. We also found that HOTAIR regulates glucose uptake in macrophages during LPS-induced inflammation and its knockdown decreases LPS-induced increased glucose uptake. HOTAIR also regulates other upstream regulators of glucose metabolism such as PTEN and HIF1α, suggesting its multimodal functions in glucose metabolism. Overall, our study demonstrated that lncRNA HOTAIR plays key roles in LPS-induced Glut1 expression and glucose uptake by activating NF-kB and hence HOTAIR regulates metabolic programming in immune cells potentially to meet the energy needs during the immune response.

scholarly journals The neurorepellent, Slit2, prevents macrophage lipid loading by inhibiting CD36-dependent binding and internalization of oxidized low-density lipoprotein

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bushra Yusuf ◽  
Ilya Mukovozov ◽  
Sajedabanu Patel ◽  
Yi-Wei Huang ◽  
Guang Ying Liu ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Super Resolution ◽  
Low Density ◽  
Dependent Manner ◽  
Oxidized Low Density Lipoprotein ◽  
Cortical Actin ◽  
Cytoskeletal Remodeling ◽  
Atherosclerotic Lesions ◽  
Modified Lipoproteins

AbstractAtherosclerosis is characterized by retention of modified lipoproteins, especially oxidized low density lipoprotein (oxLDL) within the sub-endothelial space of affected blood vessels. Recruited monocyte-derived and tissue-resident macrophages subsequently ingest oxLDL by binding and internalizing oxLDL via scavenger receptors, particularly CD36. The secreted neurorepellent, Slit2, acting through its transmembrane receptor, Roundabout-1 (Robo-1), was previously shown to inhibit recruitment of monocytes into nascent atherosclerotic lesions. The effects of Slit2 on oxLDL uptake by macrophages have not been explored. We report here that Slit2 inhibits uptake of oxLDL by human and murine macrophages, and the resulting formation of foam cells, in a Rac1-dependent and CD36-dependent manner. Exposure of macrophages to Slit2 prevented binding of oxLDL to the surface of cells. Using super-resolution microscopy, we observed that exposure of macrophages to Slit2 induced profound cytoskeletal remodeling with formation of a thick ring of cortical actin within which clusters of CD36 could not aggregate, thereby attenuating binding of oxLDL to the surface of cells. By inhibiting recruitment of monocytes into early atherosclerotic lesions, and the subsequent binding and internalization of oxLDL by macrophages, Slit2 could represent a potent new tool to combat individual steps that collectively result in progression of atherosclerosis.

scholarly journals Low-density-lipoprotein-receptor-related protein (LRP) interacts with a GTP-binding protein

1998 ◽  
Vol 336 (2) ◽  
pp. 381-386 ◽  
Author(s):  
Lothar GORETZKI ◽  
Barbara M. MUELLER
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Dependent Manner ◽  
Related Protein ◽  
Gtp Binding ◽  
Density Lipoprotein Receptor ◽  
Dose Dependent ◽  
Lipoprotein Receptor Related Protein

The low-density-lipoprotein-receptor-related protein (LRP) binds and internalizes numerous ligands, including lipoproteins, proteinase–inhibitor complexes and others. We have shown previously that LRP-mediated ligand internalization is dependent on cAMP-dependent protein kinase (PKA) activity. Here, we investigated whether ligation of LRP increases the intracellular cAMP level and PKA activity via a stimulatory GTP-binding protein. Treatment of LRP-expressing cell lines with the LRP ligands lactoferrin or urokinase-type plasminogen activator caused a significant elevation in cAMP and stimulated PKA activity in a dose-dependent manner. Addition of the 39 kDa receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, blocked the lactoferrin-induced increase in PKA activity, demonstrating a requirement for ligand binding to LRP. Incubation of cell membrane fractions with lactoferrin increased GTPase activity in a time- and dose-dependent manner, and treatment with LRP ligands suppressed cholera-toxin-mediated ADP-ribosylation of the Gsα subunit of a heterotrimeric G-protein. Affinity precipitation of LRP with RAP resulted in co-precipitation of two isoforms of Gsα from detergent extracts. We thus conclude that LRP is a signalling receptor that associates directly with a stimulatory heterotrimeric G-protein and activates a downstream PKA-dependent pathway.

scholarly journals Very-Low-Density Lipoprotein Receptor Fragment Shed from HeLa Cells Inhibits Human Rhinovirus Infection

1998 ◽  
Vol 72 (12) ◽  
pp. 10246-10250 ◽  
Author(s):  
Thomas C. Marlovits ◽  
Christina Abrahamsberg ◽  
Dieter Blaas
Keyword(s):  
Hela Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Intercellular Adhesion Molecule ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Dependent Manner ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor

ABSTRACT The large family of human rhinoviruses, the main causative agents of the common cold, is divided into the major and the minor group based on receptor specificity. Major group viruses attach to intercellular adhesion molecule 1 (ICAM-1), a member of the immunoglobulin superfamily, whereas minor group viruses use low-density lipoprotein receptors (LDLR) for cell entry. During early attempts aimed at isolating the minor group receptor, we discovered that a protein with virus binding activity was released from HeLa cells upon incubation with buffer at 37°C (F. Hofer, B. Berger, M. Gruenberger, H. Machat, R. Dernick, U. Tessmer, E. Kuechler, and D. Blaas, J. Gen. Virol. 73:627–632, 1992). In light of the recent discovery of several new members of the LDLR family, we reinvestigated the nature of this protein and present evidence for its being derived from the human very-low density lipoprotein receptor (VLDLR). A soluble VLDLR fragment encompassing the eight complement type repeats and representing the N-terminal part of the receptor was then expressed in the baculovirus system; both the shed protein and the recombinant soluble VLDLR bind minor group viruses and inhibit viral infection of HeLa cells in a concentration-dependent manner.

scholarly journals Silencing the Very Low-density Lipoprotein Receptor (VLDLR) Prevents Obesity Associated with Excess Lipid Deposition (P21-040-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Thomas Fungwe ◽  
Samuel Besong ◽  
Tahar Hajri
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Lipid Deposition ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Cardiac Lipotoxicity

Abstract Objectives Obesity is associated with an insulin resistant state, characterized by abnormalities in lipid metabolism, a leading cause of morbidity and mortality in cardiovascular diseases (CVD). Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of apolipoprotein E triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity associated lipotoxicity is not well understood. Methods In the current study, lean WT, VLDLR-deficient (VLDLR−/−), genetically obese leptin-deficient (Lepob/ob), and leptin–VLDLR double-null (Lepob/ob/VLDLR−/−) mice were used to determine the impact of VLDLR deficiency on obesity-induced cardiac lipotoxicity. Results The results showed that insulin sensitivity and glucose uptake were reduced in the hearts of Lepob/ob mice, and at the same time, VLDLR expression was upregulated and associated with increased VLDL uptake resulting in excess lipid deposition. These changes were accompanied by upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in Lepob/ob mice reduced VLDL uptake and prevented excess lipid deposition. Moreover, VLDLR deficiency reduced superoxide overproduction and normalized glucose uptake. In isolated cardiomyocytes, VLDLR deficiency prevented VLDL-mediated induction of NOx activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. An important observation showed that Lepob/ob/VLDLR−/− mice compared to Lepob/ob mice, had significantly improved heart performance and energetic reserves. Conclusions These findings suggest that that when VLDLR is silenced (deficiency), lipid deposition is also reduced, preventing cardiac lipotoxicity in obesity. In addition, the effects may be linked to the role of VLDLR on VLDL uptake, which triggers a cascade of events leading to insulin resistance and superoxide overproduction. Funding Sources Institutional Support. Howard University, Washington DC 20059 Hackensack University Medical Center, NJ 07601

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