The Experts below are selected from a list of 21987 Experts worldwide ranked by ideXlab platform
Sadao Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Species differences of macrophage Very Low-Density-Lipoprotein (VLDL) receptor protein expression
Biochemical and biophysical research communications, 2011Co-Authors: Sadao Takahashi, Takashi Ito, Yasuo Zenimaru, Jinya Suzuki, Isamu Miyamori, Masao Takahashi, Masafumi Takahashi, Takafumi Ishida, Tatsuro Ishida, Ken-ichi HirataAbstract:Triglyceride-rich Lipoproteins (TGRLs) and Low-Density-Lipoprotein (LDL) cholesterol are independent risk factors for coronary artery disease. We have previously proposed that the Very Low-Density-Lipoprotein (VLDL) receptor is one of the receptors required for foam cell formation by TGRLs in human macrophages. However, the VLDL receptor proteins have not been detected in atherosclerotic lesions of several animal models. Here we showed no VLDL receptor protein was detected in mouse macrophage cell lines (Raw264.7 and J774.2) or in mouse peritoneal macrophages in vitro. Furthermore, no VLDL receptor protein was detected in macrophages in atherosclerotic lesions of chow-fed apoLipoprotein E-deficient or cholesterol-fed LDL receptor-deficient mice in vivo. In contrast, macrophage VLDL receptor protein was clearly detected in human macrophages in vitro and in atherosclerotic lesions in myocardial infarction-prone Watanabe-heritable hyperlipidemic (WHHLMI) rabbits in vivo. There are species differences in the localization of VLDL receptor protein in vitro and in vivo. Since VLDL receptor is expressed on macrophages in atheromatous plaques of both rabbit and human but not in mouse models, the mechanisms of atherogenesis and/or growth of atherosclerotic lesions in mouse models may be partly different from those of humans and rabbits.
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deficiency of the Very low density Lipoprotein vldl receptors in streptozotocin induced diabetic rats insulin dependency of the vldl receptor
Endocrinology, 2005Co-Authors: Tadao Iwasaki, Sadao Takahashi, Yasuo Zenimaru, Jinya Suzuki, Isamu Miyamori, Masao Takahashi, Takeshi Kujiraoka, Mitsuaki Ishihara, Makoto Nagano, Hironobu NaikiAbstract:Hyperlipidemia is a common feature of diabetes and is related to cardiovascular disease. The Very Low-Density Lipoprotein receptor (VLDL-R) is a member of the Low-Density Lipoprotein receptor (LDL-R) family. It binds and internalizes triglyceride-rich Lipoproteins with high specificity. We examined the etiology of hyperlipidemia in the insulin-deficient state. VLDL-R expression in heart and skeletal muscle were measured in rats with streptozotocin (STZ)-induced diabetes. STZ rats showed severe hyperlipidemia on d 21 and 28, with a dramatic decline in VLDL-R protein in skeletal muscle (>90%), heart (∼50%) and a loss of adipose tissues itself on d 28. The reduction of VLDL-R protein in skeletal muscle could not be explained simply by a decrease at the transcriptional level, because a dissociation between VLDL-R protein and mRNA expression was observed. The expression of LDL-R and LDL-R-related protein in liver showed no consistent changes. Furthermore, no effect on VLDL-triglyceride production in liver was ...
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the Very low density Lipoprotein vldl receptor characterization and functions as a peripheral Lipoprotein receptor
Journal of Atherosclerosis and Thrombosis, 2004Co-Authors: Sadao Takahashi, Yasuo Zenimaru, Jinya Suzuki, Isamu Miyamori, Juro Sakai, Hiroaki Hattori, Takahiro Fujino, Tokuo T. YamamotoAbstract:The Very Low-Density Lipoprotein (VLDL) receptor is a member of the Low-Density Lipoprotein (LDL) receptor family. In vitro and in vivo studies have shown that VLDL receptor binds triglyceride (TG)-rich Lipoproteins but not LDL, and functions as a peripheral remnant Lipoprotein receptor. VLDL receptor is expressed abundantly in fatty acid-active tissues (heart, skeletal muscle and fat), the brain and macrophages. It is likely that VLDL receptor functions in concert with Lipoprotein lipase (LPL), which hydrolyses TG in VLDL and chylomicron. In contrast to the LDL receptor, VLDL receptor binds apoLipoprotein (apo) E2/2 VLDL particles as well as apoE3/3 VLDL, and the expression is not down-regulated by intracellular Lipoproteins. Recently, various functions of the VLDL receptor have been reported in Lipoprotein metabolism, metabolic syndrome/atherosclerosis, cardiac fatty acid metabolism, neuronal migration and angiogenesis/tumor growth. Gene therapy of VLDL receptor into the liver showed a benefit effect for Lipoprotein metabolism in both LDL receptor knockout and apoE mutant mice. Beyond its function as a peripheral Lipoprotein receptor, possibilities of its physiological function have been extended to include signal transduction, angiogenesis and tumor growth.
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The Very low density Lipoprotein (VLDL) receptor--a peripheral Lipoprotein receptor for remnant Lipoproteins into fatty acid active tissues.
Molecular and cellular biochemistry, 2003Co-Authors: Sadao Takahashi, Isamu Miyamori, Juro Sakai, Takahiro Fujino, Tokuo T. YamamotoAbstract:The VLDL (Very low density Lipoprotein) receptor is a member of the LDL (low density Lipoprotein) receptor family. The VLDL receptor binds apoLipoprotein (apo) E but not apo B, and is expressed in fatty acid active tissues (heart, muscle, adipose) and macrophages abundantly. Lipoprotein lipase (LPL) modulates the binding of triglyceride (TG)-rich Lipoprotein particles to the VLDL receptor. By the unique ligand specificity, VLDL receptor practically appeared to function as IDL (intermediate density Lipoprotein) and chylomicron remnant receptor in peripheral tissues in concert with LPL. In contrast to LDL receptor, the VLDL receptor expression is not down regulated by Lipoproteins. Recently several possible functions of the VLDL receptor have been reported in Lipoprotein metabolism, atherosclerosis, obesity/insulin resistance, cardiac fatty acid metabolism and neuronal migration. The gene therapy of VLDL receptor into the LDL receptor knockout mice liver showed a benefit effect for Lipoprotein metabolism and atherosclerosis. Further researches about the VLDL receptor function will be needed in the future.
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structure chromosome location and expression of the human Very low density Lipoprotein receptor gene
Journal of Biological Chemistry, 1994Co-Authors: Juro Sakai, Sadao Takahashi, Yutaka Kawarabayasi, Atsushi Hoshino, Yukio Miura, Hirofumi Ishii, Hiroyuki Suzuki, Tokuo YamamotoAbstract:Isolation and characterization of cDNAs encoding human Very low density Lipoprotein (VLDL) receptor revealed the presence of two forms of the receptor: one consists of five domains that resemble the low density Lipoprotein (LDL) receptor, and a variant form lacks an O-linked sugar domain. More than 96% of amino acids in the human and rabbit VLDL receptors are identical, whereas those in the LDL receptors are less conserved between the two species (76%). The human VLDL receptor gene contains 19 exons spanning approximately 40 kilobases. The exon-intron organization of the gene is almost the same as that of the LDL receptor gene, except for an extra exon that encodes an additional repeat in the ligand binding domain of the VLDL receptor. Analysis of DNA from human-rodent hybrid cells revealed that the gene is located on chromosome 9. Although the 5'-flanking region of the VLDL receptor gene contains two copies of a sterol regulatory element-1 like sequence, the levels of mRNA for the receptor in THP-1 human monocytic leukemia cells were unchanged by sterols. The 5'-untranslated region of the receptor mRNA contains a polymorphic triplet repeat found also in the fragile X syndrome gene.
Louis M Havekes - One of the best experts on this subject based on the ideXlab platform.
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bexarotene induces dyslipidemia by increased Very low density Lipoprotein production and cholesteryl ester transfer protein mediated reduction of high density Lipoprotein
Endocrinology, 2009Co-Authors: Jitske De Vriesvan Der Weij, Louis M Havekes, Willeke De Haan, Maarten Kuif, Ling H D W Oei, Jose W A Van Der Hoorn, H M G Princen, Johannes A Romijn, Johannes W A Smit, Patrick C N RensenAbstract:A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apoLipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with Very Low-Density Lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and Low-Density Lipoprotein (LDL)-C (+63%), it decreased high-density Lipoprotein (HDL)-C (-30%) and tended to decrease apoAI (-18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (-56%) as well as apoAI (-31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.
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apoav reduces plasma triglycerides by inhibiting Very low density Lipoprotein triglyceride vldl tg production and stimulating Lipoprotein lipase mediated vldl tg hydrolysis
Journal of Biological Chemistry, 2004Co-Authors: Frank G Schaap, Patrick C N Rensen, Peter J Voshol, Carlos L J Vrins, Hendrik N Van Der Vliet, Robert A F M Chamuleau, Louis M Havekes, Albert K Groen, Ko Willems Van DijkAbstract:ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 108 plaque-forming units/mouse) dose-dependently reduced plasma Very low density Lipoprotein (VLDL)-TG levels. First, we evaluated whether a reduced hepatic VLDL production contributed to the TG-lowering effect. Ad-apoa5 treatment dose-dependently diminished (29-37%) the VLDL-TG production rate without affecting VLDL particle production, suggesting that apoAV impairs the lipidation of apoB. Second, Ad-apoa5 treatment dose-dependently reduced (68-88%) the postprandial hypertriglyceridemia following an intragastric fat load, suggesting that apoAV also stimulates the Lipoprotein lipase (LPL)-dependent clearance of TG-rich Lipoproteins. Indeed, recombinant apoAV was found to dose-dependently stimulate LPL activity up to 2.3-fold in vitro. Accordingly, intravenously injected VLDL-like TG-rich emulsions were cleared at an accelerated rate concomitant with the increased uptake of emulsion TG-derived fatty acids by skeletal muscle and white adipose tissue in Ad-apoa5-treated mice. From these data, we conclude that apoAV is a potent stimulator of LPL activity. Thus, apoAV lowers plasma TG by both reducing the hepatic VLDL-TG production rate and by enhancing the lipolytic conversion of TG-rich Lipoproteins. Chemicals / CAS: Apoa5 protein, mouse; ApoLipoproteins; Lipids; Lipoprotein Lipase, EC 3.1.1.34; Lipoproteins; Lipoproteins, VLDL; Recombinant Proteins; Triglycerides; Very low density Lipoprotein triglyceride
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stimulation of lipogenesis by pharmacological activation of the liver x receptor leads to production of large triglyceride rich Very low density Lipoprotein particles
Journal of Biological Chemistry, 2002Co-Authors: Aldo Grefhorst, Peter J Voshol, Louis M Havekes, Johannes A Romijn, Vincent W Bloks, B M Elzinga, Torsten Plosch, Fjodor H Van Der Sluijs, Henkjan J Verkade, Folkert KuipersAbstract:The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist T0901317 to C57BL/6J mice (10 mg/kg/day, 4 days) is associated with massive hepatic steatosis along the entire liver lobule and a 2.5-fold increase in Very low density Lipoprotein-triglyceride (VLDL-TG) secretion. The increased VLDL-TG secretion was fully accounted for by formation of larger (129 ± 9 nm versus 94 ± 12 nm, a 2.5-fold increase of particle volume) TG-rich particles. Stimulation of VLDL-TG secretion did not lead to elevated plasma TG levels in C57BL/6J mice, indicating efficient particle metabolism and clearance. However, T0901317 treatment did lead to severe hypertriglyceridemia in mouse models of defective TG-rich Lipoprotein clearance, i.e. APOE*3-Leiden transgenic mice (3.2-fold increase) and apoE-/-LDLr-/- double knockouts (12-fold increase). Incubation of rat hepatoma McA-RH7777 cells with T0901317 also resulted in intracellular TG accumulation and enhanced TG secretion. We conclude that, in addition to raising high density Lipoprotein cholesterol concentrations, pharmacological LXR activation in mice leads to development of hepatic steatosis and secretion of atherogenic, large TG-rich VLDL particles. Chemicals/CAS: Anticholesteremic Agents; ApoLipoproteins E; Carrier Proteins; DNA-Binding Proteins; Lipids; Lipoproteins, VLDL; liver X receptor; Membrane Proteins; Phospholipid Transfer Proteins; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; Sulfonamides; T 0901317; Triglycerides; Very low density Lipoprotein triglyceride
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stimulation of lipogenesis by pharmacological activation of the liver x receptor leads to production of large triglyceride rich Very low density Lipoprotein particles
Journal of Biological Chemistry, 2002Co-Authors: Aldo Grefhorst, Peter J Voshol, Louis M Havekes, Johannes A Romijn, Vincent W Bloks, B M Elzinga, Torsten Plosch, Tineke Kok, Fjodor H Van Der Sluijs, Henkjan J VerkadeAbstract:The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist T0901317 to C57BL/6J mice (10 mg/kg/day, 4 days) is associated with massive hepatic steatosis along the entire liver lobule and a 2.5-fold increase in Very low density Lipoprotein-triglyceride (VLDL-TG) secretion. The increased VLDL-TG secretion was fully accounted for by formation of larger (129 +/- 9 nm versus 94 +/- 12 nm, a 2.5-fold increase of particle volume) TG-rich particles. Stimulation of VLDL-TG secretion did not lead to elevated plasma TG levels in C57BL/6J mice, indicating efficient particle metabolism and clearance. However, T0901317 treatment did lead to severe hypertriglyceridemia in mouse models of defective TG-rich Lipoprotein clearance, i.e. APOE*3-Leiden transgenic mice (3.2-fold increase) and apoE-/- LDLr-/- double knockouts (12-fold increase). Incubation of rat hepatoma McA-RH7777 cells with T0901317 also resulted in intracellular TG accumulation and enhanced TG secretion. We conclude that, in addition to raising high density Lipoprotein cholesterol concentrations, pharmacological LXR activation in mice leads to development of hepatic steatosis and secretion of atherogenic, large TG-rich VLDL particles.
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domains of apoLipoprotein e contributing to triglyceride and cholesterol homeostasis in vivo carboxyl terminal region 203 299 promotes hepatic Very low density Lipoprotein triglyceride secretion
Journal of Biological Chemistry, 2001Co-Authors: Kyriakos E Kypreos, Louis M Havekes, K W Van Dijk, Vassilis I ZannisAbstract:ApoLipoprotein (apo) E has been implicated in cholesterol and triglyceride homeostasis in humans. At physiological concentration apoE promotes efficient clearance of apoE-containing Lipoprotein remnants. However, high apoE plasma levels correlate with high plasma triglyceride levels. We have used adenovirus-mediated gene transfer in apoE-deficient mice (E-/-) to define the domains of apoE required for cholesterol and triglyceride homeostasis in vivo. A dose of 2 × 109 plaque-forming units of apoE4-expressing adenovirus reduced slightly the cholesterol levels of E -/- mice and resulted in severe hypertriglyceridemia, due to accumulation of cholesterol and triglyceride-rich Very low density Lipoprotein particles in plasma. In contrast, the truncated form apoE4-202 resulted in a 90% reduction in the plasma cholesterol levels but did not alter plasma triglyceride levels in the E-/- mice. ApoE secretion by cell cultures, as well as the steady-state hepatic mRNA levels in individual mice expressing apoE4 or apoE4-202, were similar. In contrast, Very low density Lipoprotein-triglyceride secretion in mice expressing apoE4, but not apoE4-202, was increased 10-fold, as compared with mice infected with a control adenovirus. The findings suggest that the amino-terminal 1-202 region of apoE4 contains the domains required for the in vivo clearance of Lipoprotein remnants. Furthermore, the carboxyl-terminal 203-299 residues of apoE promote hepatic Very low density Lipoprotein-triglyceride secretion and contribute to apoE-induced hypertriglyceridemia. Chemicals/CAS: cholesterol, 57-88-5; ApoLipoprotein E4; ApoLipoproteins E; Cholesterol, 57-88-5; DNA Primers; RNA, Messenger; Triglycerides
Nico Tjandra - One of the best experts on this subject based on the ideXlab platform.
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nuclear magnetic resonance solution structure of the recombinant fragment containing three fibrin binding cysteine rich domains of the Very low density Lipoprotein receptor
Biochemistry, 2018Co-Authors: Koyeli Banerjee, Sergiy Yakovlev, Leonid Medved, James M Gruschus, Nico TjandraAbstract:Our previous studies revealed that interaction of fibrin with the Very low density Lipoprotein (VLDL) receptor plays a prominent role in transendothelial migration of leukocytes and thereby inflammation. The major goal of our subsequent studies is to establish the structural basis for this interaction. As the first step toward this goal, we localized the fibrin-binding sites within cysteine-rich (CR) domains 2–4 of the VLDL receptor. In this study, we have made a next step toward this goal by establishing the nuclear magnetic resonance solution structure of the recombinant VLDLR(2–4) fragment containing all three fibrin-binding CR domains of this receptor. The structure revealed that all three CR domains have a similar general fold. Each domain contains a calcium-binding loop, and the loop in the CR3 domain has a unique conformation relative to the other two. Domains CR2 and CR3 interact with each other, while CR4 is flexible relative to the other two domains. In addition, analysis of the electrostatic po...
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nuclear magnetic resonance solution structure of the recombinant fragment containing three fibrin binding cysteine rich domains of the Very low density Lipoprotein receptor
Biochemistry, 2018Co-Authors: Koyeli Banerjee, Sergiy Yakovlev, Leonid Medved, James M Gruschus, Nico TjandraAbstract:Our previous studies revealed that interaction of fibrin with the Very low density Lipoprotein (VLDL) receptor plays a prominent role in transendothelial migration of leukocytes and thereby inflammation. The major goal of our subsequent studies is to establish the structural basis for this interaction. As the first step toward this goal, we localized the fibrin-binding sites within cysteine-rich (CR) domains 2-4 of the VLDL receptor. In this study, we have made a next step toward this goal by establishing the nuclear magnetic resonance solution structure of the recombinant VLDLR(2-4) fragment containing all three fibrin-binding CR domains of this receptor. The structure revealed that all three CR domains have a similar general fold. Each domain contains a calcium-binding loop, and the loop in the CR3 domain has a unique conformation relative to the other two. Domains CR2 and CR3 interact with each other, while CR4 is flexible relative to the other two domains. In addition, analysis of the electrostatic potential surface of VLDLR(2-4) revealed extended negatively charged regions in each of its CR domains. The presence of these regions suggests that they may interact with three positively charged clusters of the fibrin βN domain whose involvement in interaction with the VLDL receptor was demonstrated earlier. Altogether, these findings provide a solid background for our next step toward establishing the structural basis for fibrin-VLDL receptor interaction.
Johannes Nimpf - One of the best experts on this subject based on the ideXlab platform.
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clusterin is a ligand for apoLipoprotein e receptor 2 apoer2 and Very low density Lipoprotein receptor vldlr and signals via the reelin signaling pathway
Journal of Biological Chemistry, 2014Co-Authors: Christian Leeb, Christine Eresheim, Johannes NimpfAbstract:Abstract Clusterin, also known as apoLipoprotein J, is a multifunctional glycoprotein with the capacity to interact with a wide range of molecules. Although clusterin has been implicated in a broad spectrum of physiological and pathological processes, such as Alzheimers disease or cancer, its precise functions remain elusive. Here we report, that clusterin binds to apoLipoprotein E receptor 2 (ApoER2) and Very low density Lipoprotein receptor (VLDLR) and is internalised by cells expressing either one of these receptors. Binding of clusterin to these receptors triggers a Reelin-like signal in cells expressing disabled-1 (Dab1). It induces phosphorylation of Dab1 which leads to activation of PI3K/Akt and n-cofilin but in contrast to Reelin, it does not activate Notch. Cell proliferation and neuroblast chain formation in subventricular zone (SVZ) explants are compromised when clusterin, which is present in the subventricular zone, is blocked in vitro. These data suggest that in the subventricular zone where Reelin is not present but ApoER2, VLDLR, and Dab1, clusterin might be involved in maintaining neurogenesis in vivo.
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clusterin is a ligand for apoLipoprotein e receptor 2 apoer2 and Very low density Lipoprotein receptor vldlr and signals via the reelin signaling pathway
Journal of Biological Chemistry, 2014Co-Authors: Christian Leeb, Christine Eresheim, Johannes NimpfAbstract:Clusterin, also known as apoLipoprotein J, is a multifunctional glycoprotein with the capacity to interact with a wide range of molecules. Although clusterin has been implicated in a broad spectrum of physiological and pathological processes, such as Alzheimer disease or cancer, its precise functions remain elusive. Here we report, that clusterin binds to apoLipoprotein E receptor 2 (ApoER2) and Very low density Lipoprotein receptor (VLDLR) and is internalized by cells expressing either one of these receptors. Binding of clusterin to these receptors triggers a Reelin-like signal in cells expressing disabled-1 (Dab1). It induces phosphorylation of Dab1, which leads to activation of PI3K/Akt and n-cofilin. Cell proliferation and neuroblast chain formation in subventricular zone (SVZ) explants are compromised when clusterin, which is present in the subventricular zone, is blocked in vitro. These data suggest that in the subventricular zone where Reelin is not present but ApoER2, VLDLR, and Dab1, clusterin might be involved in maintaining neurogenesis in vivo.
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differential functions of apoer2 and Very low density Lipoprotein receptor in reelin signaling depend on differential sorting of the receptors
Journal of Biological Chemistry, 2010Co-Authors: Sarah Duit, Sophia M Blake, Wolfgang J Schneider, Harald Mayer, Johannes NimpfAbstract:ApoER2 and Very low density Lipoprotein (VLDL) receptor transmit the Reelin signal into target cells of the central nervous system. To a certain extent, both receptors can compensate for each other, and only the loss of both receptors results in the reeler phenotype, which is characterized by a gross defect in the architecture of laminated brain structures. Nevertheless, both receptors also have specific distinct functions, as corroborated by analyses of the subtle phenotypes displayed in mice lacking either ApoER2 or VLDL receptor. The differences in their function(s), however, have not been defined at the cellular level. Here, using a panel of chimeric receptors, we demonstrate that endocytosis of Reelin and the fate of the individual receptors upon stimulation are linked to their specific sorting to raft versus non-raft domains of the plasma membrane. VLDL receptor residing in the non-raft domain endocytoses and destines Reelin for degradation via the clathrin-coated pit/clathrin-coated vesicle/endosome pathway without being degraded to a significant extent. Binding of Reelin to ApoER2, a resident of rafts, leads to the production of specific receptor fragments with specific functions of their own and to degradation of ApoER2 via lysosomes. These features contribute to a receptor-specific fine tuning of the Reelin signal, leading to a novel model that emphasizes negative feedback loops specifically mediated by ApoER2 and VLDL receptor, respectively.
Leonid Medved - One of the best experts on this subject based on the ideXlab platform.
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nuclear magnetic resonance solution structure of the recombinant fragment containing three fibrin binding cysteine rich domains of the Very low density Lipoprotein receptor
Biochemistry, 2018Co-Authors: Koyeli Banerjee, Sergiy Yakovlev, Leonid Medved, James M Gruschus, Nico TjandraAbstract:Our previous studies revealed that interaction of fibrin with the Very low density Lipoprotein (VLDL) receptor plays a prominent role in transendothelial migration of leukocytes and thereby inflammation. The major goal of our subsequent studies is to establish the structural basis for this interaction. As the first step toward this goal, we localized the fibrin-binding sites within cysteine-rich (CR) domains 2–4 of the VLDL receptor. In this study, we have made a next step toward this goal by establishing the nuclear magnetic resonance solution structure of the recombinant VLDLR(2–4) fragment containing all three fibrin-binding CR domains of this receptor. The structure revealed that all three CR domains have a similar general fold. Each domain contains a calcium-binding loop, and the loop in the CR3 domain has a unique conformation relative to the other two. Domains CR2 and CR3 interact with each other, while CR4 is flexible relative to the other two domains. In addition, analysis of the electrostatic po...
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nuclear magnetic resonance solution structure of the recombinant fragment containing three fibrin binding cysteine rich domains of the Very low density Lipoprotein receptor
Biochemistry, 2018Co-Authors: Koyeli Banerjee, Sergiy Yakovlev, Leonid Medved, James M Gruschus, Nico TjandraAbstract:Our previous studies revealed that interaction of fibrin with the Very low density Lipoprotein (VLDL) receptor plays a prominent role in transendothelial migration of leukocytes and thereby inflammation. The major goal of our subsequent studies is to establish the structural basis for this interaction. As the first step toward this goal, we localized the fibrin-binding sites within cysteine-rich (CR) domains 2-4 of the VLDL receptor. In this study, we have made a next step toward this goal by establishing the nuclear magnetic resonance solution structure of the recombinant VLDLR(2-4) fragment containing all three fibrin-binding CR domains of this receptor. The structure revealed that all three CR domains have a similar general fold. Each domain contains a calcium-binding loop, and the loop in the CR3 domain has a unique conformation relative to the other two. Domains CR2 and CR3 interact with each other, while CR4 is flexible relative to the other two domains. In addition, analysis of the electrostatic potential surface of VLDLR(2-4) revealed extended negatively charged regions in each of its CR domains. The presence of these regions suggests that they may interact with three positively charged clusters of the fibrin βN domain whose involvement in interaction with the VLDL receptor was demonstrated earlier. Altogether, these findings provide a solid background for our next step toward establishing the structural basis for fibrin-VLDL receptor interaction.
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interaction of fibrin with the Very low density Lipoprotein vldl receptor further characterization and localization of the vldl receptor binding site in fibrin βn domains
Biochemistry, 2017Co-Authors: Sergiy Yakovlev, Leonid MedvedAbstract:Our recent study revealed that fibrin and the Very Low-Density Lipoprotein receptor (VLDLR) interact with each other through a pair of fibrin βN-domains and CR domains of the receptor and this interaction promotes transendothelial migration of leukocytes and thereby inflammation. The major objectives of this study were to further clarify the molecular mechanism of fibrin–VLDLR interaction and to identify amino acid residues in the βN-domains involved in this interaction. Our binding experiments with the (β15–66)2 fragment, which corresponds to a pair of fibrin βN-domains, and the VLDLR(1–8) fragment, consisting of eight CR domains of VLDLR, revealed that interaction between them strongly depends on ionic strength and chemical modification of all Lys or Arg residues in (β15–66)2 results in abrogation of this interaction. To identify which of these residues are involved in the interaction, we mutated all Lys or Arg residues in each of the three positively charged Lys/Arg clusters of the (β15–66)2 fragment, ...
