The Insulin-Stimulated Cell Surface Presentation of Low Density Lipoprotein Receptor-Related Protein in 3T3-L1 Adipocytes Is Sensitive to Phosphatidylinositide 3-Kinase Inhibition

Ko, Kerry W.S.; Avramoglu, Rita Kohen; McLeod, Roger S.; Vukmirica, Jelena; Yao, Zemin

doi:10.1021/bi001797+

Cited by 33 publications

(33 citation statements)

References 46 publications

(59 reference statements)

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“…7). Treatment with wortmannin greatly reduced Cy3 fluorescence in neurons, in agreement with reports that recruitment of LRP to the cell surface from endosomal storage pools is almost completely inhibited by wortmannin (31).…”

Section: Trafficking Of Anionic Liposomes In Hippocampal Neusupporting

confidence: 78%

Low-density Lipoprotein Receptor-related Protein Mediates the Endocytosis of Anionic Liposomes in Neurons

Lakkaraju¹,

Rahman²,

Dubinsky³

2002

Journal of Biological Chemistry

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We have recently demonstrated that anionic liposomes efficiently introduce foreign DNA into postmitotic neurons and other cell types (Lakkaraju, A., Dubinsky, J. M., Low, W. C., and Rahman, Y.-E. (2001) J. Biol. Chem. 276, 32000 -32007). To investigate the mechanism of liposome uptake, we followed the internalization of anionic liposome-encapsulated Cy3-labeled oligonucleotides (AL-Cy3ONs) by hippocampal neurons using confocal microscopy. Uptake of ALCy3ONs was widespread and time-and temperature-dependent, indicative of receptor-mediated endocytosis. The low-density lipoprotein receptor-related protein (LRP) was crucial for anionic liposome endocytosis because the receptor-associated protein or an anti-LRP antibody inhibited internalization, and fibroblasts lacking LRP did not internalize AL-Cy3ONs. Using selective endocytosis inhibitors, we found that liposome endocytosis and intracellular transport required clathrin, dynamin, an intact cytoskeletal network, and phosphatidylinositol 3-kinase activity. Cy3ONs did not significantly colocalize with recycling endosomal/ lysosomal markers and entered neuronal nuclei within 1-3 h of incubation. Approximately 50% of the internalized liposomal phospholipids were recycled back to the cell surface, in keeping with the fluidity of their acyl chains. Liposome endocytosis did not require heparan sulfate proteoglycans or cause calcium influx into neurons. Thus, constitutive endocytosis of anionic liposomes by LRP utilizes only one component, in contrast to the more involved heparan sulfate proteoglycan-LRP pathway implicated in the pathogenesis of Alzheimer's disease.Endocytosis in neurons has mainly been studied in the context of synaptic vesicle recycling (1) and the regulation of neurotransmitter receptor numbers in the post-synaptic membrane (2). Constitutive endocytosis also occurs in neurons, albeit at a slower rate than in non-polarized or mitotically active cells. Growth factors and hormones modulate the rate of constitutive endocytosis of neurotransmitter receptors as well as receptors involved in nutrient acquisition and metabolism. Neurotrophins such as nerve growth factor and bone-derived neurotrophic factor increase both the recruitment of clathrin to the plasma membrane and the rate of constitutive endocytosis of transferrin in hippocampal neurons (3).Little is known, however, about the mechanisms of internalization of exogenous macromolecules such as phospholipids and nucleic acids in neurons. Insight into the interactions between neurons and these molecules would further our understanding of lipid and DNA transport pathways and provide potential therapeutic advantages. We have recently designed and developed an anionic liposome vector (composed of the anionic phospholipid dioleoylphosphatidylglycerol and the zwitterionic phospholipid dioleoylphosphatidylcholine) for oligonucleotide delivery to neurons. Antisense oligonucleotides targeted to the p53 tumor suppressor mRNA, delivered to neurons via anionic liposomes, efficiently protected hippocampal neurons fr...

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Section: Trafficking Of Anionic Liposomes In Hippocampal Neusupporting

confidence: 78%

Low-density Lipoprotein Receptor-related Protein Mediates the Endocytosis of Anionic Liposomes in Neurons

Lakkaraju¹,

Rahman²,

Dubinsky³

2002

Journal of Biological Chemistry

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“…The binding of RAP to the plasma membrane of adipocytes was increased by treating rats with insulin, and binding reached a maximum after 4-to 5-min treatment (Descamps et al, 1993). It has been reported that increased cell surface localization of LRP-1 is associated with activation of phosphatidylinositide 3-kinase, and insulin probably stimulates the rate of LRP-1 translocation from the intracellular pool to the plasma membrane because the internalization rate of LRP-1 was not reduced by insulin treatment (Ko et al, 2001). It has been also reported that insulin treatment induces the caveolar localization of LRP-1, which may increase the stable localization on the plasma membrane (Zhang et al, 2004).…”

Section: Discussionmentioning

confidence: 94%

Insulin Facilitates the Hepatic Clearance of Plasma Amyloid β-Peptide (1–40) by Intracellular Translocation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP-1) to the Plasma Membrane in Hepatocytes

2007

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The hepatic clearance of amyloid ␤-peptide (1-40) [A␤(1-40)] from plasma, which is largely mediated by low-density lipoprotein receptor-related protein (LRP-1), is suggested to play a role in preventing A␤(1-40) accumulation in the brain. Epidemiological investigations suggest a high incidence of cerebral A␤ deposition in insulin-resistant type II diabetes mellitus. The purpose of this study was to clarify the effect of insulin on the hepatic clearance of A␤(1-40). LRP-1 expression on the hepatic plasma membrane was increased in a time-dependent manner by portal infusion of insulin and was 2.2-fold greater than that in nontreated controls after a 10-min infusion, whereas the expression in whole lysate was not affected by insulin treatment. The apparent hepatic uptake of [125 I]A␤(1-40) was also induced by insulin in a time-dependent manner. The increase in [125 I]A␤(1-40) uptake by insulin was concentrationdependent (EC 50 ϭ 230 pM) and was completely abolished by receptor-associated protein (2 M), an LRP-1 inhibitor. In conclusion, plasma insulin facilitates LRP-1 translocation to the hepatic plasma membrane from the intracellular pool, resulting in significant enhancement of hepatic A␤(1-40) uptake from the circulating blood. The presently proposed mechanism would explain the epidemiological results demonstrating that type II diabetes mellitus is a risk factor of Alzheimer's disease.

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“…The PI 3-kinase inhibitors wortmannin (WM) and LY294002 (LY) reduced the rate of Tf recycling (28 -33), as did microinjected antibodies that inhibit p110␣, the catalytic subunit of one of the class I PI 3-kinases (34). Conversely, activation of class I PI 3-kinase activity by the insulin receptor accelerates the recycling of TfR and other receptors (35,36). Recently, it was reported that WM inhibits rapid, but not slow, recycling of the TfR and the AT 1 angiotensin II receptor (32).…”

mentioning

confidence: 99%

Endocytosed Transferrin Receptors Recycle via Distinct Dynamin and Phosphatidylinositol 3-Kinase-dependent Pathways

Dam

Broeke

Jansen

et al. 2002

Journal of Biological Chemistry

126

114

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Recycling of endocytosed membrane proteins involves passage through early endosomes and recycling endosomes. Previously, we demonstrated a role for clathrin-coated vesicles in transferrin receptor recycling. These clathrin-coated vesicles are formed from recycling endosomes in a process that was inhibited in dynamin-1 G273D -overexpressing cells. Here we show a second transferrin recycling pathway, which requires phosphatidylinositol 3-kinase activity. Two unrelated phosphatidylinositol 3-kinase inhibitors, LY294002 and wortmannin, retained endocytosed transferrin in early endosomes but did not affect transfer through recycling endosomes. The inhibitory effects of LY294002 and dynamin-1 G273D on transferrin recycling were additive. In combination with brefeldin A, a drug that prevents the formation of clathrin-coated buds at recycling endosomes, LY294002 inhibited transferrin recycling synergistically. Collectively, these data indicate two distinct recycling pathways. One pathway involves transfer from early endosomes to recycling endosomes, from where clathrin/dynamin-coated vesicles provide for further transport, whereas the other route bypasses recycling endosomes and requires phosphatidylinositol 3-kinase activity.

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The Insulin-Stimulated Cell Surface Presentation of Low Density Lipoprotein Receptor-Related Protein in 3T3-L1 Adipocytes Is Sensitive to Phosphatidylinositide 3-Kinase Inhibition

Cited by 33 publications

References 46 publications

Low-density Lipoprotein Receptor-related Protein Mediates the Endocytosis of Anionic Liposomes in Neurons

Low-density Lipoprotein Receptor-related Protein Mediates the Endocytosis of Anionic Liposomes in Neurons

Insulin Facilitates the Hepatic Clearance of Plasma Amyloid β-Peptide (1–40) by Intracellular Translocation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP-1) to the Plasma Membrane in Hepatocytes

Endocytosed Transferrin Receptors Recycle via Distinct Dynamin and Phosphatidylinositol 3-Kinase-dependent Pathways

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